EP4169908A1 - Formulations d'enzalutamide - Google Patents

Formulations d'enzalutamide Download PDF

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Publication number
EP4169908A1
EP4169908A1 EP22197255.7A EP22197255A EP4169908A1 EP 4169908 A1 EP4169908 A1 EP 4169908A1 EP 22197255 A EP22197255 A EP 22197255A EP 4169908 A1 EP4169908 A1 EP 4169908A1
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Prior art keywords
enzalutamide
dispersion
polymer
concentration
amorphous
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EP22197255.7A
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German (de)
English (en)
Inventor
Douglas Alan Lorenz
Sanjay Konagurthu
Randy J. Wald
Jason A. Everett
Sheila Matz
Yuuki Takaishi
Toshiro Sakai
Ryousuke IRIE
Shinsuke Oba
Hiroyasu TOYOTA
Koji Nishimura
Atsushi Kanbayashi
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Astellas Pharma Inc
Medivation Prostate Therapeutics LLC
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Astellas Pharma Inc
Medivation Prostate Therapeutics LLC
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Application filed by Astellas Pharma Inc, Medivation Prostate Therapeutics LLC filed Critical Astellas Pharma Inc
Priority to EP23205739.8A priority Critical patent/EP4324527A3/fr
Publication of EP4169908A1 publication Critical patent/EP4169908A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
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    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
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    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin

Definitions

  • This disclosure relates to solid formulations of enzalutamide. More particularly, this disclosure relates to solid formulations comprising amorphous enzalutamide, and to pharmaceutical compositions comprising a solid dispersion containing enzalutamide and at least one polymer. Furthermore, this disclosure relates to methods for manufacturing such formulations and compositions, and to their use.
  • Enzalutamide is an androgen receptor signaling inhibitor.
  • the chemical name is 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl ⁇ -2-fluoro-N-methylbenzamide.
  • the structural formula is:
  • Enzalutamide is used as an agent for treating castration-resistant prostate cancer. See, e.g., US 7,709,517 .
  • Enzalutamide is provided commercially as a soft capsule (brand name "XTANDI ® ") filled with a liquid comprising 40 mg of enzalutamide per one capsule and pharmaceutical excipients. The daily dosage is 160 mg, and a patient therefore needs to take four capsules daily.
  • a suitable single tablet of reasonable size comprising the prescribed amount of enzalutamide and having suitable and advantageous solubility and/or dissolution stability and absorption would be advantageous as a suitable alternative to soft capsules.
  • the patent literature reports a sparingly soluble compound held on a gel-forming water-soluble polymer such as hydroxypropyl methylcellulose or hydroxypropylcellulose, as a solid dispersion, wherein the composition contains a salt substance to improve a disintegration time and dissolution profile and the like. See, e.g., US2002/0031547 .
  • Use of hydroxypropylmethylcellulose acetate succinate in a pharmaceutical composition comprising a sparingly soluble compound, prepared by a spray drying method also has been reported to improve aqueous solubility and/or bioavailability. See, e.g., US2002/0009494 .
  • Solubilization of a specific drug depends on its chemical structure and physical properties; therefore, whether any particular polymer will solubilize a specific drug is not necessarily predictable. It is often difficult and time-consuming to select polymers which achieve improved solubilization, because the drug-polymer interaction is poorly understood. For example, addition of polymers may actually speed dissolution of a drug, rather than provide enhanced concentration.
  • Enzalutamide is an androgen receptor signaling inhibitor.
  • the chemical name is 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl ⁇ -2-fluoro- N- methylbenzamide.
  • the structural formula is:
  • Enzalutamide is used as an agent for treating castration-resistant prostate cancer who have received docetaxel therapy; enzalutamide also is disclosed for treating breast cancer, prostate cancer, benign prostate hyperplasia and ovarian cancer; See, e.g., U.S. Patent 7,709,517 .
  • the present disclosure provides a solid dispersion having the properties such as improvement solubility and absorption of enzalutamide, and a pharmaceutical composition containing the solid dispersion which has dissolution stability.
  • the present disclosure provides a method for making pharmaceutical composition which has dissolution stability of enzalutamide.
  • a pharmaceutical composition which improves solubility and absorption of enzalutamide (2) a pharmaceutical composition which has rapid disintegrating property and dispersibility of enzalutamide when said pharmaceutical composition (tablet and the like)is used, and (3) a process of manufacturing the pharmaceutical composition which has said effect, can be provided.
  • compositions provide unusually large enhancements in aqueous concentration in an environment of use. These compositions also provide the opportunity to dose the entire daily therapeutic dose of enzalutamide in a single dosage unit, by improving the oral bioavailability of the drug.
  • enzalutamide is amorphous (i.e., in a non-crystalline state). Amorphous enzalutamide dissolves more quickly and to a greater extent than crystalline enzalutamide in an aqueous use environment, such as an aqueous dissolution medium of an in vitro dissolution test (e.g., phosphate buffered saline or model fasted duodenal fluid or simulated gastric fluid) or the in vivo environment of the stomach or small intestine.
  • an aqueous dissolution medium of an in vitro dissolution test e.g., phosphate buffered saline or model fasted duodenal fluid or simulated gastric fluid
  • This enhanced dissolution results in higher enzalutamide oral bioavailability, compared to crystalline drug.
  • An example of a crystalline form of enzalutamide is Form A, characterized by the powder x-ray diffraction pattern designated 'Bulk Crystalline Drug' in FIG
  • enzalutamide is greater than 80% amorphous ( i.e., containing less than 20% crystalline enzalutamide). In some embodiments, enzalutamide is greater than 90% amorphous ( i.e., containing less than 10% crystalline enzalutamide). In some embodiments, enzalutamide is greater than 95% amorphous ( i.e., containing less than 5% crystalline enzalutamide). In some embodiments, enzalutamide exhibits no crystalline character when measured by powder x-ray diffraction, by low angle x-ray scattering, by 13 C-NMR, or by 19 F-NMR.
  • Amorphous enzalutamide may be prepared by any known means, including spray-drying, hot melt extrusion, and precipitation from solution on addition of a non-solvent.
  • enzalutamide The exact amount (effective dose) of enzalutamide will vary from subject to subject, depending on, for example, the species, age, weight and general or clinical condition of the subject, the severity or mechanism of any disorder being treated, the particular agent or vehicle used, the method and scheduling of administration, and the like.
  • Treatment may involve daily or multi- daily doses of compound(s) over a period of a few days to months, or even years.
  • a suitable dose will be in the range of from about 0.001 to about 100 mg/kg, e.g., from about 0.01 to about 100 mg/kg of body weight per day, such as above about 0.1 mg per kilogram, or in a range of from about 1 to about 10 mg per kilogram body weight of the recipient per day.
  • a suitable dose may be about 1 mg/kg, 10 mg/kg, or 50 mg/kg of body weight per day.
  • Enzalutamide conveniently administered in unit dosage form; for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to 1000 mg, 10 to 200 mg, or 40 to 160 mg of enzalutamide per unit dosage form.
  • Enzalutamide may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator.
  • compositions comprise amorphous enzalutamide and a concentration-enhancing polymer. In some embodiments, compositions comprise amorphous enzalutamide and more than one concentration-enhancing polymer.
  • Amorphous enzalutamide and a concentration-enhancing polymer may be physically mixed, that is the two materials, as separate powders, may be blended by methods known in the pharmaceutical arts, including dry-blending, dry-granulation, and wet granulation.
  • compositions comprise solid amorphous dispersions of enzalutamide and a concentration-enhancing polymer.
  • at least a major portion of the enzalutamide in the composition is amorphous.
  • the term "a major portion" of the enzalutamide means that at least 60% of the enzalutamide in the composition is in the amorphous form, rather than the crystalline form.
  • the enzalutamide in the dispersion is substantially amorphous.
  • substantially amorphous means that the amount of the enzalutamide in crystalline form does not exceed about 20%.
  • the enzalutamide in the dispersion is "almost completely amorphous, meaning that the amount of enzalutamide in the crystalline form does not exceed about 10%.
  • Amounts of crystalline enzalutamide may be measured by powder X-ray diffraction, low angle x-ray scattering, differential scanning calorimetry (DSC), solid state 19F-NMR, solid state 13C-NMR, or any other standard quantitative measurement.
  • Compositions may contain from about 1 to about 80 wt % enzalutamide, depending on the dose of the drug and the effectiveness of the concentration-enhancing polymer. Enhancement of aqueous enzalutamide concentrations and relative bioavailability are typically best at low enzalutamide levels in the dispersion, typically less than about 75 wt %. In some embodiments, dispersions comprise greater than 20wt% and less than 75wt% enzalutamide. In some embodiments, dispersions comprise greater than 25wt% and less than 75wt% enzalutamide. In some embodiments, dispersions comprise greater than 50wt% and less than 70wt% enzalutamide.
  • Amorphous enzalutamide can exist within the solid amorphous dispersion as a pure phase, as a solid solution of enzalutamide homogeneously distributed throughout the polymer, or any combination of these states or states that lie intermediate between them.
  • the dispersion is substantially homogeneous so that the amorphous enzalutamide is dispersed as homogeneously as possible throughout the polymer.
  • substantially homogeneous means that the fraction of enzalutamide that is present in relatively pure amorphous domains within the solid dispersion is relatively small, on the order of less than 20%, and in some embodiments, less than 10% of the total amount of enzalutamide.
  • the solid amorphous dispersion may have some enzalutamide-rich domains.
  • the dispersion itself has a single glass transition temperature (Tg) which demonstrates that the dispersion is substantially homogeneous. This contrasts with a simple physical mixture of pure amorphous enzalutamide particles and pure amorphous polymer particles which generally displays two distinct Tgs, one that of the enzalutamide and one that of the polymer.
  • Tg as used herein is the characteristic temperature where a glassy material, upon gradual heating, undergoes a relatively rapid (e.g., 10 to 100 seconds) physical change from a glass state to a rubber state.
  • the Tg of an amorphous material such as a polymer, drug or dispersion can be measured by several techniques, including by a dynamic mechanical analyzer (DMA), a dilatometer, dielectric analyzer, and by a differential scanning calorimeter (DSC).
  • DMA dynamic mechanical analyzer
  • DSC differential scanning calorimeter
  • the exact values measured by each technique can vary somewhat but usually fall within 10° to 30°C of each other. Regardless of the technique used, when an amorphous dispersion exhibits a single Tg, this indicates that the dispersion is substantially homogenous.
  • Dispersions that are substantially homogeneous generally are more physically stable and have improved concentration-enhancing properties and, in turn, improved bioavailability, relative to nonhomogeneous dispersions.
  • compositions comprising the enzalutamide and a concentration-enhancing polymer provide enhanced concentration of the dissolved enzalutamide in in vitro dissolution tests. It has been determined that enhanced drug concentration in in vitro dissolution tests in Model Fasted Duodenal (MFD) solution (MFDS) or Phosphate Buffered Saline (PBS) is a good indicator of in vivo performance and bioavailability.
  • An appropriate PBS solution is an aqueous solution comprising 20 mM sodium phosphate (Na2HPO4), 47 mM potassium phosphate (KH2PO4), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH 6.5 with NaOH.
  • An appropriate MFD solution is the same PBS solution wherein additionally is present 7.3 mM sodium taurocholic acid and 1.4 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine.
  • a composition can be dissolution-tested by adding it to MFD or PBS solution and agitating to promote dissolution.
  • the amount of composition added to the solution in such a test is an amount that, if all the drug in the composition dissolved, would produce an enzalutamide concentration that is at least about 2-fold and, in some embodiments, at least 5-fold the equilibrium solubility of the crystalline enzalutamide alone in the test solution.
  • compositions provide a Maximum Drug Concentration (MDC) that is at least about 2-fold the maximum concentration of a control composition comprising an equivalent quantity of crystalline enzalutamide but free from the concentration-enhancing polymer, during the first 90 minutes after dosing the dispersion into the in vitro medium.
  • MDC Maximum Drug Concentration
  • a composition provides an MDC of at least about 20 ⁇ g/mL.
  • the comparison composition is conventionally crystalline enzalutamide.
  • the MDC of enzalutamide achieved with the compositions is at least about 5-fold the maximum concentration of the control composition.
  • the MDC of enzalutamide achieved with the compositions is at least about 10-fold the maximum concentration of the control composition.
  • compositions when tested in the in vitro test described above, exhibit a enzalutamide concentration one hour after reaching C max which is at least 80% of the C max concentration, where Cmax is the maximum enzalutamide concentration achieved in the in vitro test.
  • compositions provide in an aqueous use environment a enzalutamide concentration versus time Area Under The Curve (AUC 90 ), for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to the use environment, that is at least 2-fold the AUC 90 of a control composition comprising an equivalent quantity of undispersed crystalline enzalutamide.
  • the compositions provide in an aqueous use environment a concentration versus time AUC 90 , for any period of at least 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to the use environment, that is at least about 5-fold, in some embodiments at least about 10-fold, that of a control composition as described above.
  • Such large enhancements in aqueous concentration versus time AUC 90 values are surprising given the extremely low aqueous solubility and hydrophobicity of enzalutamide.
  • compositions meet both the C max and AUC 90 criteria when tested in vitro.
  • the in vitro test to evaluate enhanced drug concentration in aqueous solution can be conducted by (1) adding with agitation a sufficient quantity of control composition, that is, the crystalline enzalutamide alone, to the in vitro test medium, typically MFD or PBS solution, to determine the maximum concentration of the enzalutamide achieved under the conditions of the test; (2) adding with agitation a sufficient quantity of test composition (e.g., the enzalutamide and polymer) in an equivalent test medium, such that if all the enzalutamide dissolved, the theoretical concentration of enzalutamide would exceed the observed maximum concentration of enzalutamide by a factor of about 20; and (3) comparing the measured MDC and/or aqueous concentration versus time AUC 90 of the test composition in the test medium with the maximum concentration, and/or the aqueous concentration versus time AUC 90 of the control composition.
  • control composition typically MFD or PBS solution
  • the amount of test composition or control composition used is an amount such that if all of the enzalutamide dissolved, the test enzalutamide concentration would be at least about 20-fold that of the control enzalutamide concentration.
  • the concentration of dissolved enzalutamide is typically measured as a function of time by sampling the test medium and plotting enzalutamide concentration in the test medium vs. time so that the MDC can be ascertained.
  • the MDC is taken to be the maximum value of dissolved enzalutamide measured over the duration of the test.
  • the aqueous concentration of the enzalutamide versus time AUC 90 is calculated by integrating the concentration versus time curve over any 90-minute time period between the time of introduction of the composition into the aqueous use environment (time equals zero) and 270 minutes following introduction to the use environment (time equals 270 minutes).
  • the time interval used to calculate AUC 90 is from time equals zero to time equals 90 minutes.
  • the AUC 90 over any 90-minute time period described above of a composition meets this criterion, it is encompassed within the compositions described in this disclosure.
  • the time period 270 min is chosen because of its physiological relevance. Drug absorption in mammals generally occurs in the small intestine, and the small intestinal transit time in humans is approximately 4.5 hr, or 270 min.
  • enzalutamide/polymer dispersions In the in vivo situation, for example after oral dosing to a human, it is important that undissolved enzalutamide/polymer dispersion be capable of dissolving and resupplying the gastrointestinal fluid with dissolved drug as drug is removed from the system by absorption through the gastrointestinal wall into the bloodstream.
  • the capacity of a dispersion to carry on this resupply function may be tested in vitro in a so-called "membrane test.”
  • enzalutamide/polymer dispersions have high capacity to support transmembrane flux in the in vitro membrane test.
  • compositions when dosed orally to a human or other mammal, provide an area under the plasma enzalutamide concentration versus time curve (AUC) that is at least about 1.25-fold that observed when a control composition comprising an equivalent quantity of crystalline drug is dosed. It is noted that such compositions can also be said to have a relative bioavailability of at least about 1.25.
  • compositions dosed orally to a human or other animal provide a plasma enzalutamide AUC that is at least about 2-fold that observed when a control composition comprising an equivalent quantity of crystalline drug is dosed.
  • the in vivo AUC is AUC 0-7days , as described below.
  • the compositions can be evaluated in either in vitro or in vivo tests, or both.
  • Relative bioavailability of enzalutamide in the dispersions can be tested in vivo in animals or humans using conventional methods for making such a determination.
  • An in vivo test such as a crossover pharmacokinetic study, may be used to determine whether a composition of enzalutamide and concentration-enhancing polymer (or a composition comprised of amorphous enzalutamide without a concentration-enhancing polymer) provides an enhanced relative bioavailability compared with a control composition comprised of crystalline enzalutamide but no polymer as described above.
  • test composition of enzalutamide and polymer is dosed to half a group of test subjects and, after an appropriate washout period (at least 42 days) the same subjects are dosed with a "control composition” that comprises an equivalent quantity of crystalline enzalutamide with no concentration-enhancing polymer present.
  • control composition that comprises an equivalent quantity of crystalline enzalutamide with no concentration-enhancing polymer present.
  • the other half of the group is dosed with the control composition first, followed by the test composition.
  • the relative bioavailability is measured as the area under the plasma drug concentration versus time curve (AUC) determined for the test group divided by the plasma AUC provided by the control composition.
  • AUC plasma drug concentration versus time curve
  • this test/control ratio is determined for each subject, and then the ratios are averaged over all subjects in the study.
  • determinations of AUC can be made by plotting the plasma concentration of drug along the ordinate (y-axis) against time along the abscissa (x-axis), and using the trapez
  • one embodiment is one in which the relative bioavailability of the test composition is at least about 1.25 relative to a control composition comprised of crystalline enzalutamide but with no concentration-enhancing polymer as described above. (That is, the in vivo AUC provided by the test composition is at least about 1.25-fold the in vivo AUC provided by the control composition.)
  • the relative bioavailability of the test composition is at least about 2, relative to a control composition composed of crystalline enzalutamide but with no concentration-enhancing polymer present, as described above.
  • the determination of AUCs is a well-known procedure and is described, for example, in Welling, "Pharmacokinetics Processes and Mathematics," ACS Monograph 185 (1986).
  • the enzalutamide test and control compositions should be dosed at a 160 mg dose to a cohort of at least 24 subjects in the fasted state. Blood samples should be collected at 0 time (pre-dose), and at post-dose times 15, 30, and 45 minutes; and at 1, 2, 3, 4, 6, 8, and 12 hours; and at 0 and 12 hours on day 2; and at 0 hours on days 3, 5, and 7 (where 0 hours on days 2, 3, 5, and 7 correspond to the time of day when dosing occurred on day 1).
  • Relative bioavailability is measured using AUC 0-7days .
  • the absolute value of the AUC 0-7days is also used to determine if a dispersion formulation falls within compositions of this disclosure; i.e., pharmaceutical compositions comprising a solid amorphous dispersion of enzalutamide and a concentration-enhancing polymer, which when dosed to a cohort of 24 or more humans at a dose of 160 mg provides a mean area under the plasma enzalutamide concentration vs. time curve from the time of dosing to 7 days after dosing, AUC 0-7days , which is greater than 150 ⁇ g•hr/ml.
  • This constraint applies to other doses as well, providing a plasma AUC 0-7days which is greater than (150 ⁇ g•hr/ml)/(160 mg) or more generally greater than 0.94 ⁇ g•hr/ml•mg, where mg refers to the weight of the enzalutamide dose.
  • This disclosure provides a pharmaceutical composition comprising a solid amorphous dispersion of enzalutamide and a concentration-enhancing polymer, said dispersion when dosed to a cohort of 24 or more humans at a dose of 160 mg providing a mean maximum plasma enzalutamide concentration C max which is greater than 2 ⁇ g/ml, In some embodiments, greater than 2.5 ⁇ g/ml.
  • C max is greater than (2 ⁇ g/ml)/(160 mg), where mg refers to the weight of the enzalutamide dose.
  • C max is greater than (2.5 ⁇ g/ml)/(160 mg); this constraint can be expressed as providing a C max greater than 12.5 ng/ml•mg. In some embodiments, C max is greater than 15.6 ng/ml•mg.
  • Concentration-enhancing polymers suitable for use in the compositions are be inert, in the sense that they do not chemically react with enzalutamide, are pharmaceutically acceptable (i . e . are non-toxic), and have at least some solubility in aqueous solution at physiologically relevant pHs ( e.g. 1-8).
  • the concentration-enhancing polymer can be neutral or ionizable, and should have an aqueous-solubility of at least 0.1 mg/mL over at least a portion of the pH range of 1-8.
  • a polymer is a "concentration-enhancing polymer" if it meets at least one, or, in some embodiments, both, of the following conditions.
  • the first condition is that the concentration-enhancing polymer increases the in vitro MDC of enzalutamide in the environment of use relative to a control composition consisting of an equivalent amount of crystalline enzalutamide but no polymer. That is, once the composition is introduced into an environment of use, the polymer increases the aqueous concentration of enzalutamide relative to the control composition.
  • the polymer increases the MDC of enzalutamide in aqueous solution by at least 2-fold relative to a control composition; in some embodiments, by at least 5-fold; in some embodiments, by at least 10-fold.
  • the second condition is that the concentration-enhancing polymer increases the AUC 90 of the enzalutamide in the in vitro environment of use relative to a control composition consisting of enzalutamide but no polymer as described above. That is, in the environment of use, the composition comprising the enzalutamide and the concentration-enhancing polymer provides an area under the concentration versus time curve (AUC 90 ) for any period of 90 minutes between the time of introduction into the use environment and about 270 minutes following introduction to the use environment that is at least 2-fold that of a control composition comprising an equivalent quantity of enzalutamide but no polymer.
  • the AUC provided by the composition is at least 5-fold; in some embodiments, at least 10-fold that of the control composition.
  • Concentration-enhancing polymers may be cellulosic or non-cellulosic.
  • the polymers may be neutral or ionizable in aqueous solution.
  • polymers are ionizable and cellulosic.
  • polymers are ionizable cellulosic polymers.
  • polymers are "amphiphilic" in nature, meaning that the polymer has hydrophobic and hydrophilic portions.
  • the hydrophobic portion may comprise groups such as aliphatic or aromatic hydrocarbon groups.
  • the hydrophilic portion may comprise either ionizable or non-ionizable groups that are capable of hydrogen bonding such as hydroxyls, carboxylic acids, esters, amines or amides.
  • the relative contents of hydrophobic, ionizable hydrophilic, and non-ionizable hydrophilic groups in the polymer can be optimized to provide improved functionality as a concentration-enhancing polymer.
  • Amphiphilic polymers may have relatively strong interactions with enzalutamide and may promote the formation of various types of polymer/drug assemblies in the use environment.
  • the repulsion of the like charges of ionized groups of such polymers may serve to limit the size of the polymer/drug assemblies to the nanometer or submicron scale.
  • such polymer/drug assemblies may comprise hydrophobic enzalutamide clusters surrounded by the polymer with the polymer's hydrophobic regions turned inward towards the enzalutamide and the hydrophilic regions of the polymer turned outward toward the aqueous environment.
  • the polar functional groups of the polymer may associate, for example, via hydrogen bonds, with polar groups of the enzalutamide.
  • the hydrophilic regions of the polymer would include the ionized functional groups.
  • Such polymer/drug assemblies in solution may well resemble charged polymeric micellar-like structures.
  • the inventors have observed that such amphiphilic polymers, particularly ionizable cellulosic polymers, have been shown to improve the MDC and/or AUC 90 of enzalutamide in aqueous solution in vitro relative to crystalline control compositions free from such polymers.
  • amphiphilic polymers can greatly enhance the maximum concentration of enzalutamide obtained when enzalutamide is dosed to a use environment.
  • such amphiphilic polymers interact with enzalutamide to prevent the precipitation or crystallization of the enzalutamide from solution despite its concentration being substantially above its equilibrium concentration.
  • the compositions when the compositions are solid amorphous dispersions of enzalutamide and the concentration-enhancing polymer, the compositions provide a greatly enhanced drug concentration, particularly when the dispersions are substantially homogeneous.
  • the maximum drug concentration may be 5-fold and often more than 10-fold the equilibrium concentration of the crystalline enzalutamide.
  • Such enhanced enzalutamide concentrations in turn lead to substantially enhanced relative bioavailability for enzalutamide.
  • One class of polymers comprises neutral non-cellulosic polymers, including, but not limited to, vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, and cyclicamido polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidone; polyvinylpyrrolidone vinyl acetate; and polyethylene polyvinyl alcohol copolymers.
  • neutral non-cellulosic polymers including, but not limited to, vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy, and cyclicamido polyvinyl alcohols that have at least a portion of their repeat units in the unhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinyl pyrrolidon
  • Another class of polymers comprises ionizable non-cellulosic polymers, including, but not limited to, carboxylic acid-functionalized vinyl polymers, such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the EUDRAGITS ® manufactured by Rohm Tech Inc., of Maiden, Mass.; amine-functionalized polyacrylates and polymethacrylates; proteins; and carboxylic acid functionalized starches such as starch glycolate.
  • carboxylic acid-functionalized vinyl polymers such as the carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as the EUDRAGITS ® manufactured by Rohm Tech Inc., of Maiden, Mass.
  • amine-functionalized polyacrylates and polymethacrylates such as the EUDRAGITS ® manufactured by Rohm Tech Inc., of Maiden, Mass.
  • proteins and carboxylic acid functionalized starches such as starch glycolate.
  • Non-cellulosic polymers that are amphiphilic are copolymers of a relatively hydrophilic and a relatively hydrophobic monomer. Examples include acrylate and methacrylate copolymers. Commercial grades of such copolymers include the EUDRAGITS ® , which are copolymers of methacrylates and acrylates; and graft copolymers of polyethyleneglycol, polyvinylcaprolactam, and polyvinylacetate, one commercially available version of a graft copolymer known as SOLUPLUS ® .
  • polymers comprise ionizable and neutral cellulosic polymers with at least one ester- and/or ether-linked substituent, in which the polymer has a degree of substitution of at least 0.1 for each substituent.
  • ether-linked substituents are recited prior to "cellulose" as the moiety attached to the ether group; for example, "ethylbenzoic acid cellulose” has ethoxybenzoic acid substituents.
  • ester-linked substituents are recited after "cellulose” as the carboxylate; for example, "cellulose phthalate” has one carboxylic acid of each phthalate moiety ester-linked to the polymer and the other carboxylic acid unreacted.
  • a polymer name such as "cellulose acetate phthalate” (CAP) refers to any of the family of cellulosic polymers that have acetate and phthalate groups attached via ester linkages to a significant fraction of the cellulosic polymer's hydroxyl groups.
  • the degree of substitution of each substituent group can range from 0.1 to 2.9 as long as the other criteria of the polymer are met.
  • “Degree of substitution” refers to the average number of the three hydroxyls per saccharide repeat unit on the cellulose chain that have been substituted. For example, if all of the hydroxyls on the cellulose chain have been phthalate substituted, the phthalate degree of substitution is 3.
  • cellulosic polymers that have additional substituents added in relatively small amounts that do not substantially alter the performance of the polymer.
  • Amphiphilic cellulosics may be prepared by substituting the cellulose at any or all of the 3 hydroxyl substituents present on each saccharide repeat unit with at least one relatively hydrophobic substituent.
  • Hydrophobic substituents may be essentially any substituent that, if substituted to a high enough level or degree of substitution, can render the cellulosic polymer essentially aqueous insoluble.
  • Hydrophilic regions of the polymer can be either those portions that are relatively unsubstituted, since the unsubstituted hydroxyls are themselves relatively hydrophilic, or those regions that are substituted with hydrophilic substituents.
  • hydrophobic substitutents examples include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; or ester-linked alkyl groups such as acetate, propionate, butyrate, etc.; and ether- and/or ester-linked aryl groups such as phenyl, benzoate, or phenylate.
  • Hydrophilic groups include ether- or ester-linked nonionizable groups such as the hydroxy alkyl substituents hydroxyethyl, hydroxypropyl, and the alkyl ether groups such as ethoxyethoxy or methoxyethoxy.
  • hydrophilic substituents are those that are ether- or ester-linked ionizable groups such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or sulfonates.
  • One class of cellulosic polymers comprises neutral polymers, meaning that the polymers are substantially non-ionizable in aqueous solution.
  • Such polymers contain non-ionizable substituents, which may be either ether-linked or ester-linked.
  • exemplary ether-linked non-ionizable substituents include: alkyl groups, such as methyl, ethyl, propyl, butyl, etc.; hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.; and aryl groups such as phenyl.
  • ester-linked non-ionizable groups include: alkyl groups, such as acetate, propionate, butyrate, etc.; and aryl groups such as phenylate.
  • alkyl groups such as acetate, propionate, butyrate, etc.
  • aryl groups such as phenylate.
  • the polymer may need to include a sufficient amount of a hydrophilic substituent so that the polymer has at least some water solubility at any physiologically relevant pH of from 1 to 8.
  • Exemplary non-ionizable polymers that may be used as the polymer include: hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.
  • neutral cellulosic polymers are those that are amphiphilic.
  • Exemplary polymers include hydroxypropyl methyl cellulose and hydroxypropyl cellulose acetate, where cellulosic repeat units that have relatively high numbers of methyl or acetate substituents relative to the unsubstituted hydroxyl or hydroxypropyl substituents constitute hydrophobic regions relative to other repeat units on the polymer.
  • cellulosic polymers comprise polymers that are at least partially ionizable at physiologically relevant pH and include at least one ionizable substituent, which may be either ether-linked or ester-linked.
  • exemplary ether-linked ionizable substituents include: carboxylic acids, such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, the various isomers of alkoxyphthalic acid such as ethoxyphthalic acid and ethoxyisophthalic acid, the various isomers of alkoxynicotinic acid such as ethoxynicotinic acid, and the various isomers of picolinic acid such as ethoxypicolinic acid, etc.; thiocarboxylic acids, such as thioacetic acid; substituted phenoxy groups, such as hydroxyphenoxy, etc.; amines, such as aminoethoxy
  • ester linked ionizable substituents include: carboxylic acids, such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and the various isomers of pyridinedicarboxylic acid, etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxy groups, such as amino salicylic acid; amines, such as natural or synthetic amino acids, such as alanine or phenylalanine; phosphates, such as acetyl phosphate; and sulfonates, such as acetyl sulfonate.
  • carboxylic acids such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and the various isomers of pyridinedicarboxylic acid, etc.
  • thiocarboxylic acids such as thiosuccinate
  • substituted phenoxy groups such as amino salicylic acid
  • amines such as
  • aromatic-substituted polymers to also have the requisite aqueous solubility, it is also desirable that sufficient hydrophilic groups such as hydroxypropyl or carboxylic acid functional groups be attached to the polymer to render the polymer aqueous soluble at least at pH values where any ionizable groups are ionized.
  • the aromatic group may itself be ionizable, such as phthalate or trimellitate substituents.
  • Exemplary cellulosic polymers that are at least partially ionized at physiologically relevant pHs include: hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropy
  • a particularly desirable subset of cellulosic ionizable polymers are those that possess both a carboxylic acid functional aromatic substituent and an alkylate substituent and thus are amphiphilic.
  • Exemplary polymers include cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxylpropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate phthalate (HPMCAP), hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl methyl
  • cellulosic ionizable polymers are those that possess a nonaromatic carboxylate substituent.
  • Exemplary polymers include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methyl cellulose acetate succinate, hydroxyethyl methyl cellulose succinate, and hydroxyethyl cellulose acetate succinate.
  • cellulosic polymers that are aqueous insoluble in their nonionized state but are aqueous soluble in their ionized state perform particularly well.
  • enteric polymers include, for example, hydroxypropylmethylcellulose acetate succinate (HPMCAS) and certain grades of hydroxypropyl methyl cellulose acetate phthalate (HPMCAP) and cellulose acetate trimellitate (CAT).
  • HPMCAS hydroxypropylmethylcellulose acetate succinate
  • HPMCAP hydroxypropyl methyl cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • concentration-enhancing polymers for use in dispersions with enzalutamide are hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulosephthalate (HPMCP), polyvinylpyrrolidonevinylacetate (PVP-VA), copolymers of methacrylic acid and methylmethacrylate (approximate 1:1 ratio) available as EUDRAGIT L-100 ® , and graft copolymers of polyethyleneglycol, polyvinylcaprolactam, and polyvinylacetate, one commercially available version of a graft copolymer is known as SOLUPLUS ® .
  • the enzalutamide/polymer dispersion may contain one or more lipophilic microphase-forming materials, comprising surfactants and lipidic mesophase-forming materials, or mixtures thereof.
  • lipophilic microphase-forming materials are sulfonated hydrocarbons and their salts, such as dioctylsodiumsulfocuccinate and sodium laurylsulfate; polyoxyethylene sorbitan fatty acid esters, such as polysorbate-80 and polysorbate-20; polyoxyethylene alkyl ethers; polyoxyethylene castor oil; polyoxyethylene (-40 or - 60) hydrogenated castor oil; tocopheryl polyethyleneglycol 1000 succinate; glyceryl polyethyleneglycol-8 caprylate/caprate; polyoxyethylene-32 glyceryl laurate; polyoxyethylene fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycolized glycerides; long
  • the enzalutamide/polymer dispersion contains less than 30% by weight of lipophilic microphase-forming materials. In some embodiments, the enzalutamide/polymer dispersion contains less than 20% by weight of lipophilic microphase-forming materials. In some embodiments, the enzalutamide/polymer dispersion contains less than 10% by weight of lipophilic microphase-forming materials. In some embodiments, the enzalutamide/polymer dispersion contains less than 5% by weight of lipophilic microphase-forming materials.
  • the enzalutamide remain, to the extent possible, in the amorphous state.
  • Tg glass-transition temperature
  • the Tg of the amorphous state of the dispersion be at least 40°C.
  • the Tg of the amorphous state of the dispersion is at least 60°C.
  • the polymer have a high Tg.
  • Exemplary high Tg concentration-enhancing polymers are HPMCAS, HPMCP, CAP, CAT.
  • the polymer is not particularly limited, so long as enzalutamide can be carried as the solid dispersion. In some embodiments, the polymer is not particularly limited, so long as enzalutamide can be an amorphous state.
  • the polymer include polyvinyl pyrrolidone (PVP), polyethyleneoxide (PEO), poly(vinyl pyrrolidone-co-vinyl acetate), polymethacrylates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polycaprolactam, polylactic acid, polyglycolic acid, poly(lactic-glycolic)acid, lipids, cellulose, pullulan, dextran, maltodextrin, hyaluronic acid, polysialic acid, chondroitin sulfate, heparin, fucoidan, pentosan polysulfate, spirulan, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (H
  • the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).
  • the polymers are hydroxypropyl methylcellulose acetate succinate (HPMCAS) and/or hydroxypropyl methyl cellulose (HPMC). These polymers may be added alone, or as mixtures thereof.
  • hydroxypropyl methylcellulose acetate succinate (HPMCAS) is hydroxypropylmethlycellulose acetate succinate M-grade (HPMCAS-M). Examples of hydroxypropylmethlycellulose acetate succinate M-grade include HPMCAS-MG (Shin-Etsu Chemical Co., Ltd.).
  • Dispersions of enzalutamide and concentration-enhancing polymer may be made according to any known process which results in at least a major portion (at least 60%) of the enzalutamide being in the amorphous state.
  • Exemplary mechanical processes include milling and hot-melt extrusion; melt processes include high temperature fusion, solvent modified fusion and melt-congeal processes; and solvent processes include non-solvent precipitation, spray coating and spray-drying.
  • the dispersions may be made by any of these processes, the dispersions generally have their maximum bioavailability and stability when the enzalutamide is dispersed in the polymer such that it is substantially amorphous and substantially homogeneously distributed throughout the polymer.
  • Particularly effective methods for forming solid amorphous dispersions of enzalutamide and concentration-enhancing polymers are solvent processing and hot melt extrusion.
  • the dispersions In general, as the degree of homogeneity of the dispersion increases, the enhancement in the aqueous concentration of enzalutamide and relative bioavailability increases as well. Given the low aqueous solubility and bioavailability of crystalline enzalutamide, it is highly preferred for the dispersions to be as homogeneous as possible. Thus, most preferred are dispersions having a single glass transition temperature, which indicates a high degree of homogeneity.
  • substantially amorphous and substantially homogeneous dispersions are made by any of the methods described above.
  • dispersions are formed by "solvent processing," in which enzalutamide and a polymer are dissolved in a common solvent.
  • “Common” here means that the solvent, which can be a mixture of compounds, will simultaneously dissolve the drug and the polymer(s). After both the enzalutamide and the polymer have been dissolved, the solvent is rapidly removed by evaporation or by mixing with a non-solvent.
  • Exemplary processes are spray-drying, spray-coating (pan-coating, fluidized bed coating, etc.), and precipitation by rapid mixing of the polymer and drug solution with CO 2 , water, or some other non-solvent.
  • removal of the solvent results in a solid dispersion which is substantially homogeneous.
  • the enzalutamide is dispersed as homogeneously as possible throughout the polymer and can be thought of as a solid solution of enzalutamide in the polymer(s).
  • the dispersion may be thermodynamically stable, meaning that the concentration of enzalutamide in the polymer is at or below its equilibrium value.
  • the composition may be a supersaturated solid solution where the enzalutamide concentration in the dispersion polymer(s) is above its equilibrium value.
  • the solvent may be removed through the process of spray-drying.
  • spray-drying is used conventionally and broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a container (spray-drying apparatus) where there is a strong driving force for evaporation of solvent from the droplets.
  • the strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of solvent in the spray-drying apparatus well below the vapor pressure of the solvent at the temperature of the drying droplets. This is accomplished by either (1) maintaining the pressure in the spray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2) mixing the liquid droplets with a warm drying gas; or (3) both.
  • at least a portion of the heat required for evaporation of solvent may be provided by heating the spray solution.
  • Solvents suitable for spray-drying can be any organic compound in which enzalutamide and polymer are mutually soluble.
  • the solvent is also volatile with a boiling point of 150°C or less.
  • the solvent should have relatively low toxicity and be removed from the dispersion to a level that is acceptable according to The International Committee on Harmonization (ICH) guidelines. Removal of solvent to this level may require a processing step such as tray-drying subsequent to the spray-drying or spray-coating process.
  • ICH International Committee on Harmonization
  • Solvents include alcohols such as methanol, ethanol, n-propanol, iso-propanol, and butanol; ketones such as acetone, methyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propylacetate; and various other solvents such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Lower volatility solvents such as dimethyl acetamide or dimethylsulfoxide can also be used.
  • Non-aqueous solvents comprise less than about 10 wt % water; in some embodiments, less than 1 wt % water.
  • solvents for spray drying enzalutamide/polymer solutions are acetone, ethanol, methanol, mixtures thereof, and mixtures with water.
  • the temperature and flow rate of the drying gas is chosen so that the polymer/drug-solution droplets are dry enough by the time they reach the wall of the apparatus that they are essentially solid, and so that they form a fine powder and do not stick to the apparatus wall.
  • the actual length of time to achieve this level of dryness depends on the size of the droplets. Droplet sizes generally range from 1 ⁇ m to 500 ⁇ m in diameter, with 5 to 100 ⁇ m being more typical.
  • the large surface-to-volume ratio of the droplets and the large driving force for evaporation of solvent leads to actual drying times of a few seconds or less, and more typically less than 0.1 second.
  • Solidification times should be less than 100 seconds. In some embodiments, solidification time is less than a few seconds. In some embodiments, solidification time is less than 1 second. In general, to achieve this rapid solidification of the enzalutamide/polymer solution, the size of droplets formed during the spray-drying process is less than about 100 ⁇ m in diameter. The resultant solid particles thus formed are generally less than about 100 ⁇ m in diameter.
  • the solid powder typically stays in the spray-drying chamber for about 5 to 60 seconds, further evaporating solvent from the solid powder.
  • the final solvent content of the solid dispersion as it exits the dryer should be low, since this reduces the mobility of enzalutamide molecules in the dispersion, thereby improving its stability.
  • the solvent content of the dispersion as it leaves the spray-drying chamber should be less than 10 wt %. In some embodiments, the solvent content of the dispersion as it leaves the spray-drying chamber is less than 2 wt %. In some cases, it may be preferable to spray a solvent or a solution of a polymer or other excipient into the spray-drying chamber to form granules, so long as the dispersion is not adversely affected.
  • Spray-drying processes and spray-drying equipment are described generally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H. Perry, D. W. Green, J. 0. Maloney, eds.) McGraw-Hill Book Co. 1984, pages 20 54 to 20 57 . More details on spray-drying processes and equipment are reviewed by Marshall "Atomization and Spray-Drying," 50 Chem. Eng. Prog. Monogr. Series 2 (1954 ).
  • enzalutamide/polymer amorphous dispersions is achieved using hot-melt extrusion.
  • Powder mixtures of enzalutamide and concentration-enhancing polymer are heated and passed through an extruder such as a 7.5 mm MP&R extruder, which is capable of reaching 210 °C and is equipped with a 1/8 inch cylindrical die. After the extruded enzalutamide/polymer mass exits the extruder, it is milled.
  • a enzalutamide/polymer dispersion has a mean particle size less than 150 ⁇ m.
  • mean particle size is less than 50 ⁇ m.
  • concentration-enhancing polymers for use in hot-melt extruded enzalutamide/polymer solid amorphous dispersions are hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidonevinylacetate (PVP-VA).
  • the amount of concentration-enhancing polymer relative to the amount of enzalutamide present in the dispersions may vary widely.
  • the composition of enzalutamide/polymer dispersions is expressed, for example, as 25%A:HPMCAS-M, where 25%A means "25% active" and the dispersion contains 25% (by weight) enzalutamide and 75% (by weight) hydroxypropylmethlycellulose acetate succinate M-grade.
  • the enzalutamide content is generally greater than 20%A; in some embodiments, from 25%A to 75%A; in some embodiments, from 50%A to 70%A.
  • the enzalutamide/polymer ratio that yields optimum results is best determined in in vitro dissolution tests and/or in vivo bioavailability tests.
  • the ratio of the polymer to enzalutamide is not particularly limited, so long as enzalutamide can be formed the solid dispersion. In some embodiments, the ratio of the polymer to enzalutamide is not particularly limited, so long as enzalutamide can be an amorphous state.
  • the ratio of the polymer is specifically 0.5 to 7 parts by weight in some embodiments, 0.5 to 3 parts by weight in some embodiments, 1 to 3 parts by weight in some embodiments, 2 to 3 parts by weight in some embodiments, 3 to 5 parts by weight in some embodiments, and 5 parts by weight in some embodiments, with respect to 1 part by weight of enzalutamide.
  • the amount of concentration-enhancing polymer that can be used in a dosage form is often limited by the total mass requirements of the dosage form.
  • the total mass of drug and polymer may be unacceptably large for delivery of the desired dose in a single tablet or capsule.
  • Solid amorphous dispersions having fine particles, such as less than 50 ⁇ m in average particle diameter, can have poor flow characteristics. Poor flowability of a solid amorphous dispersion can lead to difficulties in handling and compressing the solid amorphous dispersion. For example, poor flowability of the solid amorphous dispersion can lead to inconsistent flow through processing equipment and/or inconsistent or incomplete filling of tablet or capsule dies, which can lead to delivery of inconsistent dosages.
  • the flow characteristics of the solid amorphous dispersion can also be dependent on the bulk specific volume of the solid amorphous dispersion.
  • the bulk specific volume of a powder is the inverse of the bulk density of a powder and can be measured as the volume occupied by a unit mass of the powder, such as in cubic centimeters per gram, when the powder is poured into a container, such as a graduated cylinder.
  • the lower the bulk specific volume of a powder the better the flowability of the particles. Improving the flowability of the solid amorphous dispersion can therefore be more desirable for a solid amorphous dispersion having a higher bulk specific volume.
  • the solid amorphous dispersion can have a bulk specific volume greater than or equal to 3 cc/g, greater than or equal to 5 cc/g, greater than or equal to 8 cc/g, from 3 to 5 cc/g, and/or from 3 to 8 cc/g.
  • High-shear mixing of the solid amorphous dispersion and a glidant can increase the uniformity of the mixed particles, such as producing an ordered mixture and/or an interactive mixture.
  • glidant means a substance that, when added to a powder, improves the flowability of the powder, such as by reducing inter-particle friction.
  • exemplary glidants include but are not limited to colloidal silicas, colloidal silicon dioxide, fumed silica, CAB-O-SIL ® M-5P, AEROSIL ® , talc, starch, and magnesium aluminum silicates.
  • a blend of the solid amorphous dispersion and the glidant using high-shear mixing can have improved flowability, as measured by Carr's Index, compared to the flowability of the solid amorphous dispersion alone.
  • the bulk density is equal to mass per volume (g/cc) of a sample before being tapped and the tapped density is equal to the mass of a sample divided by the volume of the sample after the sample is tapped for 2000 cycles in a Vankel Tap density instrument.
  • a powder having a lower Carr's Index can also be easier to compress into a tablet.
  • a mixture having a Carr's Index greater than 40% can be difficult to compress into a tablet.
  • a tablet formed from a mixture having a high Carr's Index can be more likely to crack, fracture, or otherwise fail to stick together or maintain a tablet form after compression.
  • Adding a glidant to the solid amorphous dispersion with high-shear mixing can produce a mixture having a low Carr's Index, such as below 40% and/or 35%, that is suitable for direct compression. This allows direct compression of the solid amorphous dispersion without the need to include an intermediate granulation process to decrease the Carr's Index of the mixture to a suitable level.
  • An exemplary method for forming a pharmaceutical dosage form comprises: providing a solid amorphous dispersion comprising particles wherein the particles comprise enzalutamide and a polymer, the solid amorphous dispersion having an average particle diameter of less than 50 ⁇ m; forming an ordered mixture by high-shear mixing a blend comprising the solid amorphous dispersion and a powdered glidant, the glidant having an average particle diameter of less than or equal to one-fifth the average particle diameter of the solid amorphous dispersion after high-shear mixing; and forming the pharmaceutical dosage form by at least one of directly compressing the ordered mixture to form a tablet and encapsulating the ordered mixture to form a capsule.
  • Another exemplary method of preparing a pharmaceutical dosage form comprises: providing a solid amorphous dispersion comprising particles wherein the particles comprise enzalutamide and a polymer, the solid amorphous dispersion having an average particle diameter of less than 50 ⁇ m; forming an ordered mixture comprising the solid amorphous dispersion and a glidant using high-shear mixing, the ordered mixture having a Carr's Index of less than 40%; and forming the pharmaceutical dosage form by directly compressing the ordered mixture to form a tablet or encapsulating the ordered mixture to form a capsule.
  • Another exemplary method for forming a pharmaceutical dosage form comprises: providing a solid amorphous dispersion comprising particles, the particles comprising enzalutamide and a polymer, the solid amorphous dispersion having an average particle diameter of less than 50 ⁇ m; forming a blend comprising the solid amorphous dispersion and a powdered glidant using high-shear mixing, the high-shear mixing having a Froude Number greater than 0.2; and forming the pharmaceutical dosage form by at least one of directly compressing the blend to form a tablet and encapsulating the blend to form a capsule.
  • high-shear mixing means a powder mixing process characterized by a Froude Number within a specified range, such as greater than 0.01, greater than 0.1, greater than 0.2, greater than 0.5, greater than 1, greater than 10, and/or greater than 20, for example. Where the Froude Number is not specified, the term “high-shear mixing” means a powder mixing process characterized by a Froude Number of at least 1. The term “high-shear mixing” does not include high-shear granulation using a liquid, or dissolving or dispersing a solid in a liquid.
  • low-shear mixing means a conventional mixing process that is not high-shear mixing.
  • the term "ordered mixture” means a mixture of powders having a level of uniformity that is greater than a level achievable by random mixing.
  • an ordered mixture means a mixture of a first powder having a first average particle size and a second powder having a second average particle size that is larger than the first average particle size, wherein all, substantially all or at least 90% of the particles of the first powder interact with and adhere to at least one of the plurality of the particles of the second powder.
  • an ordered mixture is also an interactive mixture.
  • the term "average particle size" means the D 50 .
  • the term D 50 means that 50 vol% of the particles have a diameter that is smaller than this, and 50 vol% of the particles have a diameter that is larger than this.
  • the average particle size may be measured using standard laser diffraction particle sizing techniques known in the art.
  • One example of an instrument to measure the particle size of the dry powders is the Masteresizer 2000, manufactured by Malvern Instruments Ltd (Worcestershire, UK).
  • the average particle diameter of the glidant after high-shear mixing is less than that of the dispersion particles. This can be determined by scanning-electron microscopy analysis of the blend. A comparison of the dispersion particles before high-shear mixing with the glidant and after high-shear mixing will show small particles of glidant on the surfaces of the dispersion particles.
  • compositions are simply the enzalutamide to be delivered and the concentration-enhancing polymer(s), the inclusion of other excipients in the composition may be useful. These excipients may be utilized with the enzalutamide and polymer composition in order to formulate the composition into tablets, capsules, suspensions, powders for suspension, creams, transdermal patches, depots, and the like.
  • the composition of enzalutamide and polymer can be added to other dosage form ingredients in essentially any manner that does not substantially alter the enzalutamide.
  • the excipients may be either physically mixed with the dispersion and/or included within the dispersion.
  • the solid dispersion (amorphous enzalutamide) comprising enzalutamide and the polymer is further mixed with one or more pharmaceutically acceptable additives to prepare a pharmaceutical composition.
  • the additives are not particularly limited, so long as they are pharmaceutically acceptable.
  • examples of the additives include a filler, a binder, a disintegrator, an acidulant, an effervescent agent, an artificial sweetener, a flavor, a lubricant, a coloring agent, a stabilizing agent, a buffer, an antioxidant, a glidant, and the like.
  • the filler may be selected from, for example, mannitol, lactose, starch, corn starch, calcium hydrogen phosphate hydrate, magnesium carbonate, calcium carbonate, purified sucrose, glucose, and the like.
  • the binder may be selected from, for example, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl cellulose, gum arabic, and the like.
  • the disintegrator may be selected from, for example, corn starch, starches, crystalline cellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, calcium silicate, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, sodium carboxymethyl starch, agar powder, crospovidone, synthetic aluminum silicate, sucrose fatty acid esters, lactose hydrate, D-mannitol, anhydrous citric acid, and the like.
  • the acidulant may be selected from, for example, citric acid, tartaric acid, malic acid, and the like.
  • the effervescent agent may be selected from, for example, sodium bicarbonate and the like.
  • the artificial sweetener may be selected from, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, and the like.
  • the flavor may be selected from, for example, lemon, lemon-lime, orange, menthol, and the like.
  • the lubricant may be selected from, for example, magnesium stearate, calcium stearate, sucrose fatty acid esters, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid, and the like.
  • the coloring agent may be selected from, for example, yellow ferric oxide, red ferric oxide, food yellow No. 4, food yellow No. 5, food red No. 3, food red No. 102, food blue No. 3, and the like.
  • the buffer may be selected from, for example, citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid, or salts thereof; glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine, or salts thereof; magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid, boric acid, or their salts; and the like.
  • the antioxidant may be selected from, for example, ascorbic acid, dibutyl hydroxytoluene, propyl gallate, and the like.
  • the glidant may be selected from, for example, light anhydrous silicic acid, titanium oxide, stearic acid, colloidal silica, colloidal 20 silicon dioxide, fumed silica, CAB-O-SIL ® M-5P, AEROSIL ® , talc, starch, and magnesium aluminum silicates and the like.
  • additives may be added alone in an appropriate amount, or as a combination of two or more thereof in appropriate amounts.
  • One very useful class of excipients to be added to the formulation after formation of the enzalutamide/polymer dispersion comprises surfactants and surface-active agents.
  • Suitable surfactants and surface-active agents are sulfonated hydrocarbons and their salts, such as dioctylsodiumsulfocuccinate and sodium laurylsulfate; polyoxyethylene sorbitan fatty acid esters, such as polysorbate-80 and polysorbate-20; polyoxyethylene alkyl ethers; polyoxyethylene castor oil; polyoxyethylene (-40 or - 60) hydrogenated castor oil; tocopheryl polyethyleneglycol 1000 succinate; glyceryl polyethyleneglycol-8 caprylate/caprate; polyoxyethylene-32 glyceryl laurate; polyoxyethylene fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycolized glycerides; long-chain fatty acids such as palmitic and stearic and
  • Such materials can be advantageously be employed to increase the rate of dissolution by facilitating wetting, thereby increasing the maximum dissolved concentration, and also to inhibit crystallization or precipitation of drug by interacting with the dissolved drug by mechanisms such as complexation, formation of inclusion complexes, formation of micelles or adsorbing to the surface of solid drug, crystalline or amorphous.
  • These surfactants may comprise up to 5% of the composition.
  • pH modifiers such as acids, bases, or buffers may also be beneficial, retarding the dissolution of the composition (e.g ., acids such as citric acid or succinic acid when the concentration-enhancing polymer is anionic) or, alternatively, enhancing the rate of dissolution of the composition (e.g ., bases such as sodium acetate or amines when the polymer is anionic).
  • binders may also be added as part of the composition itself or added by granulation via wet or mechanical or other means. These materials may comprise up to 90 wt % of the composition.
  • matrix materials examples include lactose, mannitol, xylitol, microcrystalline cellulose, calcium diphosphate, and starch.
  • disintegrants examples include sodium starch glycolate, sodium alginate, carboxy methyl cellulose sodium, methyl cellulose, and croscarmellose sodium.
  • binders examples include methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth.
  • lubricants examples include magnesium stearate and calcium stearate.
  • excipients may be employed, including those excipients well-known in the art.
  • excipients such as pigments, lubricants, flavorants, and so forth may be used for customary purposes and in typical amounts without adversely affecting the properties of the compositions.
  • excipients may be utilized in order to formulate the composition into tablets, capsules, suspensions, powders for suspension, creams, transdermal patches, and the like.
  • compositions may be delivered by a wide variety of routes, including, but not limited to, oral, nasal, rectal, and pulmonary. In some embodiments, compositions are delivered by the oral route.
  • the pharmaceutical compositions comprising the solid dispersion can be formulated into various dosage forms, including tablets, powders, fine granules, granules, dry syrups, capsules and the like as well as the solid dispersion itself.
  • the solid pharmaceutical composition is in tablet form.
  • compositions disclosed herein may also be used in a wide variety of dosage forms for administration of enzalutamide.
  • Exemplary dosage forms are powders or granules that may be taken orally either dry or reconstituted by addition of water or other liquids to form a paste, slurry, suspension or solution; tablets; capsules; multiparticulates; and pills.
  • Various additives may be mixed, ground, or granulated with the compositions disclosed herein to form a material suitable for the above dosage forms.
  • compositions may be formulated in various forms such that they are delivered as a suspension of particles in a liquid vehicle.
  • suspensions may be formulated as a liquid or paste at the time of manufacture, or they may be formulated as a dry powder with a liquid, typically water, added at a later time but prior to oral administration.
  • powders that are constituted into a suspension are often termed sachets or oral powder for constitution (OPC) formulations.
  • OPC oral powder for constitution
  • dosage forms can be formulated and reconstituted via any known procedure. The simplest approach is to formulate the dosage form as a dry powder that is reconstituted by simply adding water and agitating.
  • dispersions of enzalutamide are formulated for long-term storage in the dry state as this promotes the chemical and physical stability of the enzalutamide.
  • Various excipients and additives are combined with the compositions to form the dosage form.
  • preservatives such as sulfites (an antioxidant), benzalkonium chloride, methyl paraben, propyl paraben, benzyl alcohol or sodium benzoate
  • suspending agents or thickeners such as xanthan gum, starch, guar gum, sodium alginate, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, polyacrylic acid, silica gel, aluminum silicate, magnesium silicate, or titanium dioxide
  • anticaking agents or fillers such as silicon oxide, or lactose
  • flavorants such as natural or artificial flavors
  • sweeteners such as sugars such as sucrose, lactose, or sorbitol as well as artificial sweeteners such as aspartame or saccharin
  • wetting agents or surfactants such as various grades of polysorbate, docusate sodium, or sodium lauryl sulfate
  • solubilizers such as ethanol propylene glyco
  • pH modifiers or buffers such as carboxylic acids (including citric acid, ascorbic acid, lactic acid, and succinic acid), various salts of carboxylic acids, amino acids such as glycine or alanine, various phosphate, sulfate and carbonate salts such as trisodium phosphate, sodium bicarbonate or potassium bisulfate, and bases such as amino glucose or triethanol amine.
  • an additional concentration-enhancing polymer may be added.
  • An additional concentration-enhancing polymer may act as a thickener or suspending agent in formulations which are constituted with a liquid before dosing, and which may provide additional precipitation inhibition for all dosage forms after dosing to an aqueous use environment.
  • the overall dosage form or particles, granules or beads that make up the dosage form may have superior performance if coated with an enteric polymer to prevent or retard dissolution until the dosage form leaves the stomach.
  • enteric coating materials include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxylic acid-functionalized polymethacrylates, and carboxylic acid-functionalized polyacrylate.
  • compositions may be administered in a controlled release dosage form.
  • the composition of the enzalutamide and polymer is incorporated into an erodible polymeric matrix device.
  • an erodible matrix is meant aqueous-erodible or water-swellable or aqueous-soluble in the sense of being either erodible or swellable or dissolvable in pure water or requiring the presence of an acid or base to ionize the polymeric matrix sufficiently to cause erosion or dissolution.
  • the erodible polymeric matrix When contacted with the aqueous environment of use, the erodible polymeric matrix imbibes water and forms an aqueous-swollen gel or "matrix" that entraps the dispersion of enzalutamide and polymer.
  • the aqueous-swollen matrix gradually erodes, swells, disintegrates or dissolves in the environment of use, thereby controlling the release of the dispersion to the environment of use.
  • compositions are administered by or incorporated into a non-erodible matrix device.
  • compositions are delivered using a coated osmotic controlled release dosage form.
  • This dosage form has two components: (a) the core which contains an osmotic agent and the dispersion of enzalutamide and concentration-enhancing polymer; and (b) a non-dissolving and non-eroding coating surrounding the core, the coating controlling the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion of some or all of the core to the environment of use.
  • the osmotic agent contained in the core of this device may be an aqueous-swellable hydrophilic polymer, osmogen, or osmagent.
  • the coating is in some embodiments, polymeric, aqueous-permeable, and has at least one delivery port.
  • compositions are delivered via a coated hydrogel controlled release form having at least two components: (a) a core comprising the dispersion and a hydrogel, and (b) a coating through which the dispersion has passage when the dosage form is exposed to a use environment.
  • a drug mixture is delivered via a coated hydrogel controlled release dosage form having at least three components: (a) a composition containing the dispersion, (b) a water-swellable composition wherein the water-swellable composition is in a separate region within a core formed by the drug-containing composition and the water-swellable composition, and (c) a coating around the core that is water-permeable, water-insoluble, and has at least one delivery port therethrough.
  • the core imbibes water through the coating, swelling the water-swellable composition and increasing the pressure within the core, and fluidizing the dispersion-containing composition. Because the coating remains intact, the dispersion-containing composition is extruded out of the delivery port into an environment of use.
  • compositions may be administered as multiparticulates.
  • Multiparticulates generally refer to dosage forms that comprise a multiplicity of particles that may range in size from about 10 ⁇ m to about 2 mm, more typically about 100 ⁇ m to 1 mm in diameter.
  • Such multiparticulates may be packaged, for example, in a capsule such as a gelatin capsule or a capsule formed from an aqueous-soluble polymer such as HPMCAS, HPMC or starch or they may be dosed as a suspension or slurry in a liquid.
  • Such multiparticulates may be made by any known process, such as wet- and dry-granulation processes, extrusion/spheronization, roller-compaction, or by spray-coating seed cores.
  • wet- and dry-granulation processes the composition of enzalutamide and concentration-enhancing polymer is prepared as described above. This composition is then granulated to form multiparticulates of the desired size.
  • Other excipients such as a binder (e.g. , microcrystalline cellulose), may be blended with the composition to aid in processing and forming the multiparticulates.
  • a binder such as microcryscalline cellulose may be included in the granulation fluid to aid in forming a suitable multiparticulate.
  • the resulting particles may themselves constitute the multiparticulate dosage form or they may be coated by various film-forming materials such as enteric polymers or water-swellable or water-soluble polymers, or they may be combined with other excipients or vehicles to aid in dosing to patients.
  • film-forming materials such as enteric polymers or water-swellable or water-soluble polymers, or they may be combined with other excipients or vehicles to aid in dosing to patients.
  • the solid dispersion can be prepared by dissolving and/or suspending enzalutamide and the polymer in a pharmaceutically acceptable solvent, and removing the solvent.
  • Pharmaceutically acceptable additives can be added to the solvent which dissolved and/or suspended enzalutamide.
  • the pharmaceutically acceptable solvent is not particularly limited, so long as enzalutamide can be an amorphous state in the presence of the polymer.
  • the pharmaceutically acceptable solvent include ketones such as acetone, alcohols such as methanol, ethanol, or propanol, a mixture thereof, and a mixed solvent of water with one or more of these solvents. These pharmaceutically acceptable solvents may be used alone or as an appropriate combination of two or more thereof.
  • the amount of the pharmaceutically acceptable solvent is not particularly limited, so long as it can be dissolved and/or suspended enzalutamide.
  • a 1- to 100-fold amount (w/w) of the pharmaceutically acceptable solvent, or a 5- to 20-fold amount (w/w) of the pharmaceutically acceptable solvent in other embodiments may be contained, with respect to the total weight of enzalutamide and the polymer.
  • a method of removing the pharmaceutically acceptable solvent is not particularly limited, so long as the solvent can be removed from the liquid in which enzalutamide and the polymer are dissolved and/or suspended.
  • Examples of the method include spray drying, drying under reduced pressure, forced-air drying, and the like, and spray drying may be used in other embodiments.
  • the process of manufacturing the pharmaceutical composition or its pharmaceutical formulation is not particularly limited, so long as it can produce the desired pharmaceutical formulation by using an appropriate combination of the above methods or known methods per se.
  • the solid dispersion is mixed with one additive, or two or more additives, and known methods per se are carried out to obtain tablets, powders, fine granules, granules, dry syrups, or capsules.
  • the process of manufacturing the pharmaceutical composition or its pharmaceutical formulation is not particularly limited, so long as it can produce the desired pharmaceutical formulation by using an appropriate combination of the above methods or known methods per se.
  • the pharmaceutical composition can be produced, for example, by any known process including the steps of blending, granulation, specific size controlling, tableting, film coating and the like.
  • the solid pharmaceutical composition in the form of powders, fine granules, granules or dry syrups can be produced by a process including the steps of (1) mixing the solid dispersion with one additive or two or more additives using blender, and (2) granulating the resulting mixture by dry granulation using dry granulator.
  • these pharmaceutical additives may be added at any stage, e.g., during step (1), between steps (1) and (2), or during step (2).
  • the specific size controlling method can be adjusted the particle size of the granules.
  • the size may be adjusted 50 ⁇ m to 500 ⁇ m, 100 ⁇ m to 300 ⁇ m in another embodiment, 100 ⁇ m to 250 ⁇ m in still another embodiment using a sizing machine.
  • the granules may each be adjusted to any suitable size by being subjected to a grinding step prior to the mixing step.
  • any apparatus or means may be used as long as it generally allows pharmaceutical grinding of the drug and/or the pharmaceutical additive(s).
  • any apparatus or means may be used as long as it generally allows pharmaceutical mixing of the individual components into a uniform state.
  • the granulated product is then tabletted to produce tablets.
  • Any tableting technique may be used for this purpose as long as it generally allows pharmaceutical production of compression molded products. Examples include techniques in which a granulated product is tabulated in admixture with one additive, or two or more additives.
  • Any type of tablet machine may be used for this purpose as long as it generally allows pharmaceutical production of compression molded products. Examples include a rotary tablet machine, a single-shot tablet machine and the like.
  • the tablet hardness is set to, for example, 50 to 300 N, or alternatively, 80 to 250 N, taking into consideration handling in production, distribution, and the like of medicaments.
  • the tablet surface may be coated with a film coating.
  • Any technique may be used for this purpose as long as it generally allows pharmaceutical tablet coating. Examples include pan coating processes and the like.
  • Any type of film coating agent may be used for this purpose as long as it is generally used as a pharmaceutical additive for pharmaceutical tablet coating. Film coating agents may be added alone or in combination as appropriate in suitable amounts.
  • the coating rate is not limited in any way as long as the tablet surface can be coated.
  • Any method may be used to produce the pharmaceutical composition sdisclosed herein or a pharmaceutical formulation thereof, as long as it allows production of pharmaceutical formulations having the desired effects by the method described above or an appropriate combination of methods known per se.
  • an enzalutamide/polymer dispersion containing 55-65 wt% enzalutamide is used for manufacture of a tablet dosage form of an enzalutamide/polymer dispersion.
  • a 60%A:HPMCAS-M dispersion is used for manufacture of a tablet dosage form of an enzalutamide/polymer dispersion.
  • a useful tablet contains approximately 70% of its total weight as 60%A:HPMCAS-M dispersion, with the remainder inactive excipients, including a disintegrant.
  • a tablet comprises sodium starch glycolate (e.g., EXPLOTAB ® ) as a disintegrant.
  • a tablet comprises croscarmellose sodium (e.g., AC-DI-SOL ® ) as a disintegrant. In some embodiments, such tablets comprise 6 to 10 wt% disintegrant. In some embodiments, a tablet comprises 266.67 mg 60%A:HPMCAS-M dispersion, and 30.5 mg croscarmellose sodium, in a 381 mg tablet; this corresponds to a dispersion content of 70 wt% and a disintegrant content of 8 wt%.
  • croscarmellose sodium e.g., AC-DI-SOL ®
  • such tablets comprise 6 to 10 wt% disintegrant.
  • a tablet comprises 266.67 mg 60%A:HPMCAS-M dispersion, and 30.5 mg croscarmellose sodium, in a 381 mg tablet; this corresponds to a dispersion content of 70 wt% and a disintegrant content of 8 wt%.
  • a tablet contains approximately 55-65% of its total weight as 60%A:HPMCAS-M dispersion, with the remainder inactive excipients, including a disintegrant.
  • sodium starch glycolate e.g ., EXPLOTAB ®
  • tablets contain croscarmellose sodium (e.g ., AC-DI-SOL ® ) as a disintegrant.
  • such tablets comprise 6 to 10 wt% disintegrant.
  • a tablet of this type may comprise 266.67 mg 60%A:HPMCAS-M dispersion, and 34 mg croscarmellose sodium, in a 425 mg tablet. This corresponds to a dispersion content of 62.7 wt% and a disintegrant content of 8 wt%.
  • a tablet contains approximately 45-55% of its total weight as 60%A:HPMCAS-M dispersion, with the remainder inactive excipients, including a disintegrant.
  • sodium starch glycolate e.g ., EXPLOTAB ®
  • croscarmellose sodium e.g ., AC-DI-SOL ®
  • a tablet comprises 6 to 10 wt% disintegrant.
  • a tablet of this type may comprise 266.67 mg 60%A:HPMCAS-M dispersion, and 40 mg croscarmellose sodium, in a 500 mg tablet.
  • dispersion content 53.3 wt% and a disintegrant content of 8 wt%.
  • Larger tablets may be made, providing they contain 266.67 mg 60%A:HPMCAS-M dispersion, and at least 6 wt% disintegrant; in some embodiments, 8 wt% disintegrant.
  • Tablets comprising enzalutamide/polymer dispersions may be prepared using wet granulation, dry granulation, or direct compression. In some embodiments, dry granulation or direct compression is used.
  • tablets comprise 60%A:HPMCAS-M dispersion, the disintegrant croscarmellose sodium, and microcrystalline cellulose (e.g., AVICEL ® PH102). In some embodiments, tablets comprise 60%A:HPMCAS-M dispersion, the disintegrant croscarmellose sodium, microcrystalline cellulose (e.g ., AVICEL ® PH102), and lactose 318 Fast-Flo.
  • tablets comprise 60%A:HPMCAS-M dispersion, the disintegrant croscarmellose sodium, microcrystalline cellulose (e.g ., AVICEL ® PH102), lactose 318 Fast-Flo, and silica (e.g., CAB-O-SIL ® ).
  • An example of a 500 mg tablet formulation, manufactured by direct compression, comprises:
  • said exemplary tablet may be made larger or smaller, without significant effect on performance, by making small variations in the amount of each excipient, providing that the tablet contains sufficient 60%A:HPMCAS-M dispersion to provide a 160 mg dose of enzalutamide.
  • the relative ratios of the five listed excipients remains approximately constant.
  • compositions disclosed herein may be used to treat any condition which is subject to treatment by administering enzalutamide. Accordingly, compositions can be used to treat hyperproliferative disorders, such as prostate cancer (e.g ., hormone-refractory prostate cancer, hormone-sensitive prostate cancer), breast cancer, and ovarian cancer, in a mammal (including a human being) by administering to a mammal in need of such treatment a therapeutically effective amount of a composition disclosed herein.
  • prostate cancer e.g ., hormone-refractory prostate cancer, hormone-sensitive prostate cancer
  • breast cancer e.g., breast cancer, and ovarian cancer
  • the in vitro dissolution test to evaluate enhanced drug concentration in aqueous solution can be conducted by (1) adding with agitation a sufficient quantity of control composition, that is, the crystalline enzalutamide alone, to the in vitro test medium, typically MFD or PBS solution, to determine the maximum concentration of the enzalutamide achieved under the conditions of the test; (2) adding with agitation a sufficient quantity of test composition (e.g ., the enzalutamide and polymer) in an equivalent test medium, such that if all the enzalutamide dissolved, the theoretical concentration of enzalutamide would exceed the observed maximum concentration of enzalutamide by a factor of about 20; and (3) comparing the measured MDC and/or aqueous concentration versus time AUC 90 of the test composition in the test medium with the maximum concentration, and/or the aqueous concentration versus time AUC 90 of the control composition.
  • control composition typically MFD or PBS solution
  • the amount of test composition or control composition used is an amount such that if all of the enzalutamide dissolved, the test enzalutamide concentration would be at least about 20-fold that of the control enzalutamide concentration.
  • the concentration of dissolved enzalutamide is typically measured as a function of time by sampling the test medium and plotting enzalutamide concentration in the test medium vs. time so that the MDC can be ascertained.
  • the MDC is taken to be the maximum value of dissolved enzalutamide measured over the duration of the test.
  • the enzalutamide concentration versus time AUC 90 is calculated by integrating the concentration versus time curve over any 90-minute time period between the time of introduction of the composition into the aqueous use environment (time equals zero) and 270 minutes following introduction to the use environment (time equals 270 minutes).
  • the time interval used to calculate AUC 90 is from time equals zero to time equals 90 minutes.
  • the composition is included in compositions of this disclosure.
  • the time period 270 min is chosen because of its physiological relevance. Drug absorption in mammals generally occurs in the small intestine, and the small intestinal transit time in humans is approximately 4.5 hr, or 270 min.
  • test solution is either filtered or centrifuged.
  • Dissolved enzalutamide is typically taken as that material that either passes a 0.45 micron syringe filter or, alternatively, the material that remains in the supernatant following centrifugation. Filtration can be conducted using a 13 mm, 0.45 micron polyvinylidine difluoride syringe filter, such as the filter sold by Scientific Resources under the trademark TITAN TM . Centrifugation is typically carried out in a polypropylene microcentrifuge tube by centrifuging at 13,000 G for 60 seconds.
  • dissolved enzalutamide encompasses not only monomeric solvated enzalutamide molecules but also a wide range of species such as polymer/enzalutamide assemblies that have submicron dimensions such as enzalutamide aggregates, aggregates of mixtures of polymer and enzalutamide, micelles, polymeric micelles, colloidal particles, polymer/enzalutamide complexes, and other such enzalutamide-containing species that are present in the filtrate or supernatant in the specified dissolution test.
  • the membrane permeability test described in the Examples below is carried out as follows. A drug-permeable membrane is placed between feed and permeate reservoirs. A sufficient quantity of test composition is added to a feed test medium and placed in the feed reservoir, while a water immiscible organic solution, such as a 60/40 mixture of decanol/decane, is placed in the permeate reservoir. Samples are removed from the permeate reservoir and analyzed for the concentration of drug as a function of time. From these data the maximum flux of drug across the membrane is determined, as is the total drug recovery, defined as the percentage of the amount of drug which has crossed the membrane after 240 minutes. Further details of this membrane permeation test are disclosed in U.S. patent number 7,611,630 B2 .
  • Control 1 is crystalline enzalutamide, obtained as described in US7,709,517B2 , in which this compound is called RD162'; and "Control 2” is a 4.23 mg/ml solution of enzalutamide in LABRASOL ® (Caprylocaproyl polyoxylglycerides).
  • Amorphous enzalutamide was prepared by spray-drying a 3 wt% solution of enzalutamide dissolved in acetone using a lab-scale spray drier.
  • the lab-scale drier consisted of a 27.6-cm diameter spray drier having a diameter-to-height ratio of greater than 3.
  • the lab-scale drier was equipped with a Schlick 2.0 pressure nozzle. Heated drying gas (nitrogen) was delivered to the drying chamber through a perforated plate to provide a uniform flow of drying gas through the drying chamber.
  • the spray solution was delivered to the nozzle at a flow rate of 20 g/min and a pressure of 110 psig.
  • the atomized droplets were combined with the nitrogen drying gas, which entered the system at a flow rate of 470 g/min and a temperature of 100°C.
  • the spray-dried particles, evaporated solvent, and drying gas were removed from the spray-drying chamber at a temperature of 45°C through an outlet port and sent to a high-efficiency cyclone separator where the spray-dried particles were collected.
  • the evaporated solvent and drying gas were then sent to a filter for removal of any remaining particles before discharge.
  • a solid amorphous dispersion of 25 wt% enzalutamide and 75 wt% HPMCAS was prepared using a spray drying process as follows.
  • a spray solution was prepared by dissolving 1 wt% enzalutamide and 3 wt% HPMCAS-M in acetone. This solution was spray-dried using the lab-scale spray drier described in Example 1. The solution was delivered to a Schlick 2.0 pressure nozzle atomizer at a pressure of 114 psig. The spray solution was delivered to the spray drier at a flow rate of 20 gm/min.
  • the nitrogen drying gas was delivered to the nozzle at 102°C and at a flow rate of 470 g/min.
  • the outlet temperature of the spray dryer was 46°C.
  • the resulting spray dried particles were removed using a cyclone separator.
  • Table 2.1 The spray drying parameters are summarized in Table 2.1.
  • the "mini" spray-dryer consisted of an atomizer in the top cap of a vertically oriented 11-cm diameter stainless steel pipe.
  • the PSD-1 spray dryer is a Niro type XP Portable Spray-Dryer with a Liquid-Feed Process Vessel.
  • PXRD Diffractograms of spray-dried amorphous drug and enzalutamide/polymer dispersions, and bulk crystalline drug.
  • the dispersions were analyzed by powder X-ray diffraction (PXRD) using an AXS D8 Advance PXRD measuring device (Bruker, Inc. of Madison, Wisconsin) using the following procedure. Samples (approximately 30 to 100 mg) were packed in Lucite sample cups fitted with Si(511) plates as the bottom of the cup to give no background signal. Samples were spun in the ⁇ plane at a rate of 30 rpm to minimize crystal orientation effects.
  • the diffractograms in FIG. 1 demonstrate that spray-dried enzalutamide, a 25%A:PVP-VA64 SDD, a 25%A:HPMCAS-M SDD, and a 60%A:HPMCAS-MG SDD all are completely amorphous, characterized by the absence of sharp crystallographic x-ray peaks.
  • Example 2 In vitro dissolution studies were carried out for a subset of the formulations whose manufacture is described in Example 2. These dissolution studies utilized the Microcentrifuge Dissolution Test described above.
  • the formulations tested were amorphous enzalutamide, various enzalutamide/Polymer spray-dried dispersions (SDDs), and Controls 1 and 2.
  • SDDs enzalutamide/Polymer spray-dried dispersions
  • Controls 1 and 2 A dose of 200 ⁇ g/ml enzalutamide was chosen, in order to be 10 to 20 times higher than the solubility of crystalline enzalutamide, in order to evaluate the ability of formulations to achieve enzalutamide supersaturation and sustainment of supersaturation relative to crystalline drug.
  • the dissolution medium was Model Fasted Duodenal Solution (MFDS), which consisted of an aqueous solution comprising 20 mM Na2HPO4, 47 mM KH2PO4, 87 mM NaCl, 0.2 mM KCl, at pH 6.5 and 290 mOsm/kg, additionally containing 7.3 mM sodium taurocholic acid and 1.4 mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine.
  • Table 4.1 Microcentrifuge dissolution test data for enzalutamide spray-dried dispersions (SDDs), amorphous enzalutamide, and controls.
  • Enzalutamide Concentration ( ⁇ g/ml) 0 min 4 min 10 min 20 min 40 min 90 min 1200 min Formulation (Dispersion #) 25%A HPMCAS-M SDD (D4) 0.0 150 150 160 160 100 40%A HPMCAS-M SDD (D5) 0.0 110 86 93 110 120 100 60%A HPMCAS-M SDD (D6) 0.0 75 78 93 100 110 100 80%A HPMCAS-M SDD (D7) 0.0 87 100 130 130 130 40 25%A HPMCAS-H SDD (D8) 0.0 110 110 110 110 110 110 110 110 40%A HPMCAS-H SDD (D9) 0.0 100 110 110 110 110 110 25%A PVP VA64 SDD (D2) 0.19 110 110 110 110 110 Not Done 40%A PVP VA64 SDD (D10) 0.0 100 100 110 110 110 40 Amorphous (spray-dried) enzalutamide - BREC-0035-09B(V) 0.0 61 100 100 110 120 30 Crystalline enzalutamide (Control
  • C max and AUC 90 Microcentrifuge dissolution data (C max and AUC 90 ) for enzalutamide spray-dried dispersions (SDDs), amorphous enzalutamide, and controls.
  • Tables 4.1 and 4.2 demonstrate that amorphous enzalutamide, a Labrasol solution of enzalutamide, and various spray-dried dispersions (SDDs) of enzalutamide with the polymers HPMCAS and PVP-VA64 all exhibit a large enzalutamide supersaturation when dissolved, relative to crystalline enzalutamide, in addition to the ability to maintain this supersaturation.
  • SDDs spray-dried dispersions
  • the AUC 90 values for the SDDs in Table 4.2 are all greater than 5 times the AUC 90 for crystalline enzalutamide (Control 1).
  • the C max 90 values for the SDDs in Table 4.2 are all greater than 5 times the C max 90 for crystalline enzalutamide (Control 1).
  • Tgs Glass Transition Temperatures
  • Tg Glass transition temperatures Tg were determined for amorphous enzalutamide, and for spray-dried dispersions (SDDs) of enzalutamide with HPMCAS-M or PVP-VA64, at ⁇ 5% and 75% relative humidity (RH). Tgs were determined by modulated differential scanning calorimetry (mDSC), utilizing the following protocol. Samples (about 5 mg) were equilibrated at the desired RH overnight in an environmental chamber at ambient temperature.
  • SDDs spray-dried dispersions
  • the samples were then loaded into pans and sealed inside the environmental chamber.
  • the samples were analyzed on a Q1000 mDSC (TA Instruments, New Castle, Delaware). Samples were typically scanned over the temperature range of -40°C to 180°C, at a scan rate of 2.5°C/min, and a modulation rate of ⁇ 1.5°C/min.
  • the data sampling interval was 0.20 sec/point.
  • the Tg was calculated based on half height.
  • Tg data are presented in Table 5.1. As is generally observed, Tg decreases with increasing RH because the amorphous material is plasticized by incorporated water vapor as the %RH increases. Generally, Tg decreases approximately linearly as %RH increases. Table 5.1.
  • T g as a Function of Relative Humidity (RH) for enzalutamide SDDs
  • Amorphous (spray-dried) MDV-3100 88.5 64.0 80%A HPMCAS-M (D7) 90.4 59.3 60%A HPMCAS-M (D6) 87.1 52.0 25%A HPMCAS-M (D4) 93.1 50.7 40%A HPMCAS-M (D5) 91.3 51.9 25%A HPMCAS-H (D8) 94.0 51.2 40%A HPMCAS-H (D9) 91.1 51.2 40%A PVP VA64 (D10) 103.3 34.9 25%A PVP VA64 (D2) 105.5 30.8
  • a dispersion composition whose Tg is above the temperatures at which the product may be stored. If the product is stored at a temperature above its Tg, the amorphous drug within the dispersion will be relatively mobile and can diffuse into drug-rich patches and can crystallize. This is undesirable.
  • Typical storage challenge conditions dictated by the US Food and Drug Administration are 40°C/25%RH, 50°C/20%RH, 30°C/60%RH, and 40°C/75%RH.
  • the 25%A and 40%A enzalutamide dispersions with the concentration-enhancing polymer PVP-VA64 exhibit Tgs at 30.8°C and 34.9°C, respectively. If enzalutamide/PVP-VA dispersions encounter storage conditions above their Tgs (such as 40°C), they can possibly undergo undesirable change. Thus enzalutamide/PVP-VA dispersions should be stored in protective packaging (such as foil-foil blisters) which prevents ingress of water vapor into the dispersion.
  • Amorphous enzalutamide and MCV3100/HPMCAS dispersions have high Tgs.
  • enzalutamide/HPMCAS SDDs have a drug content less than 80%.
  • Drugs and drug formulations are sometimes dosed as aqueous suspensions, particularly for pediatric patients.
  • the ability of various enzalutamide SDDs to retain their ability to maintain drug supersaturation in vitro was assessed by using the microcentrifuge dissolution test to measure drug dissolution after suspension in 0.5% methylcellulose in water for 2 hours.
  • Methylcellulose is a standard viscosifying suspending agent which is used to maintain drug particles in suspension in oral suspension dosage forms.
  • the table below presents in vitro dissolution performance before and after suspension in 0.5% methylcellulose.
  • Table 7.1 In vitro dissolution behavior of SDDs before and after suspension for 2 hr in aqueous 0.5% methylcellulose.
  • Amorphous enzalutamide and the SDDs with HPMCAS-MG maintained their ability to effect sustained supersaturation after suspension for 2 hr in aqueous methylcellulose.
  • Incubation of a 25%A:PVPVA64 SDD for 2 hr in aqueous methylcellulose resulted in a 26% loss in supersaturation capacity, as measured by AUC 90 .
  • the MP-dissolution test measures a capability of low solubility drug formulations which is not measured in the microcentrifuge dissolution test utilized in Examples 4 and 7. This test mimics an aspect of the in vivo situation in the GI tract. In the in vivo situation, it is generally accepted that free drug in solution (i.e . individual drug molecules dissolved in the GI medium without association with formulation components) is the species which is absorbed across the gastrointestinal wall into the bloodstream. As free drug is absorbed, the formulation must be capable of supplying more free drug for absorption.
  • the membrane permeation test measures the amount of drug which crosses a polymeric membrane (as a model of the GI wall) over time, and thus reflects the ability of the formulation to resupply free drug in solution to be further passively transported across the polymeric membrane.
  • Maximum Flux is the maximum observed rate of permeation across the polymeric membrane, based on the slope of the absorption curve over any period within the 240 minute duration of the experiment, normalized for membrane area.
  • Total drug recovery is the % of the initial drug dose which has crossed the membrane when the test ended at 240 minutes. Table 8.1.
  • enzalutamide/HPMCAS SDDs have an enzalutamide content less than 80%A.
  • the data in Table 8.1 also indicate that enzalutamide SDDs with the M- and H-grades of HPMCAS perform equally well.
  • a 60%A enzalutamide SDD was prepared with each of three polymers:
  • Table 9.1 shows that the enzalutamide SDDs with HPMCP-55 and with EUDRAGIT L100 ® exhibit decreased enzalutamide concentration in solution after the 40 minute time point, while SDDs with HPMCAS and HPMC E3 Prem do not. This is reflected in the in vitro AUC 90 data shown in Table 9.2. Table 9.1. In vitro dissolution (microcentrifuge dissolution test) of various enzalutamide SDDs and crystalline enzalutamide.
  • the membrane permeation test was carried out for 60%A enzalutamide SDDs with HPMCAS-M, HPMC E3 Prem, HPMCP-55, and Eudragit-L100, as described in Example 8.
  • the data in Table 9.3 demonstrate that each of the four SDDs exhibit higher transmembrane flux than crystalline enzalutamide, and have the capacity to replace absorbed free drug.
  • the data in Table 9.3 also demonstrate that the SDDs with HPMCAS-M and HPMC E3 Prem have greater transmembrane flux and thus greater capacity to replace absorbed free drug than do SDDs with HPMCP-55 and Eudragit-L100. Table 9.3.
  • HME dispersions were produced using dry-powder blends of enzalutamide and HPMCAS-M or PVP VA at three different drug loadings: 25%A, 40%A, and 60%A.
  • a volumetric powder feeder the blends were fed at a controlled rate to a 7.5-mm MP&R TM Model ME7.5 Twin-Screw Extruder (MP&R, Winensack, NJ).
  • the extruder is capable of reaching 210°C and is equipped with a 1/8-inch cylindrical die. Extrudates were milled by hand using a mortar and pestle for subsequent testing.
  • Table 11.1 presents the extrusion temperature, the crystallinity of the dispersion (amorphous is desired), and the glass transition temperature (Tg) measured by DSC. Table 11.1. Extrusion temperature, and extrudate properties after milling with mortar and pestle Formulation (Dispersion #) Control Temp.
  • a This is the control temperature for the terminal extruder barrels and the die.
  • the actual product temperature is higher in the extruder due to additional frictional heat. It is difficult to measure the actual product temperature but was done using a temperature probe during the preparation of Dispersion D26. In that case, the extruder control temperature was 195°C and the product temperature was measured at approximately 215°C.
  • b This sample was prepared on a hot plate at a temperature higher than was possible using the MP&R extruder.
  • amorphous enzalutamide:PVP-VA64 dispersions can be prepared by HME at 25%A and 40%A.
  • Amorphous 60%A:PVP-VA64 dispersions can also be prepared if the temperature is held at 190 °C.
  • enzalutamide dispersions with HPMCAS-M were crystalline or partially crystalline, when prepared at the temperatures possible on the extruder used.
  • Preparation at 220 °C on a hot plate resulted in an amorphous 40%A:HPMCAS-M dispersion.
  • Preparation of HME dispersions of MDC3100 with HPMCAS at temperatures above 200 °C is non-optimal because HPMCAS degrades in this temperature range.
  • Dissolution of enzalutamide/polymer dispersions prepared by HME was evaluated using the microcentrifuge dissolution test, after dispersions were sieved to give various particle size ranges. Dissolution results are presented in Table 11.2. Table 11.2. Microcentrifuge dissolution test results for enzalutamide dispersions prepared by hot melt extrusion. The total amount of sample dosed was 200 mcg per ml of dissolution medium. The dissolution medium was Model Fasted Duodenal Solution (MFDS) (0.5 wt% NaTC/POPC in PBS, pH 6.5, 290 mOsm). Results for SDDs of similar composition are presented for comparison.
  • MFDS Model Fasted Duodenal Solution
  • HME dispersions with HPMCAS or PVP-VA with a particle size ⁇ 50 ⁇ m, are as efficacious as SDDs of identical composition.
  • HME dispersions with particle size 50-150 ⁇ m are also similar in efficacy to SDDs of identical composition.
  • HME dispersions with particle size 150-355 ⁇ m are generally less efficacious than SDDs in achieving and maintaining supersaturation of enzalutamide.
  • the analytes, enzalutamide, MDPC0002, and MDPC0001 and internal standards (IS), N- 13 CD 3 -enzalutamide, MDPC0002- 13 CD 3 , and MDPC0001- 13 CD 3 were extracted from 0.050 ⁇ L of rat plasma by a liquid-liquid extraction procedure. Internal standard working solution (25.0 ⁇ L) was added to all wells except the matrix blank. A 25.0- ⁇ L volume of acetonitrile was added all matrix blank samples. After adding 200 ⁇ L of 5% sodium bicarbonate in water buffer solution, the plate was vortexed for approximately 10 seconds.
  • a Tomtec Quadra 96-well pipettor was used to add 1.050 mL of methyl tert-butyl ether (MTBE) to all wells, mixed, and approximately 1.00 mL of the organic layer was transferred to a clean 96-well plate.
  • the samples were evaporated under heated nitrogen and reconstituted with 250 ⁇ L of 0.1% formic acid in methanol/water (40:60, v/v). The plate was covered and gently vortexed for approximately 10 seconds.
  • the extracts were chromatographed under reverse phase conditions on an ACE 5 C18 HPLC 5 ⁇ m, 2.1 ⁇ 30 mm column.
  • the compounds were detected and quantified by tandem mass spectrometry in positive ion mode on an MDS Sciex API 3000 equipped with a Turbo IONSPRAY ® probe. Calibration curves were obtained by performing a linear regression (weighted 1/x 2 ) of the data from the calibration standards.
  • Plasma enzalutamide concentration vs. time curves were prepared, and values for the following parameters were determined.
  • C max max is the highest enzalutamide concentration observed for each rat.
  • Tmax is the time that C max is first achieved.
  • AUC 0-72 is the area under the plasma enzalutamide concentration vs. time plot out to 72 hr post-dosing.
  • Pharmacokinetic data for the formulations studied are presented in Table 12.1.
  • Table 12.1. Mean pharmacokinetic parameters ( ⁇ standard deviation) in rats for enzalutamide formulations. Crystalline drug, amorphous drug, and SDDs were dosed in suspension in a 0.5% methylcellulose vehicle.
  • the AUC 0-72 data demonstrate that the 25%A:HPMCAS-M and 60%A:HPMCAS-M dispersions give higher bioavailability than the spray-dried amorphous drug.
  • the 60%A:HPMCAS-M dispersion is equivalent in C max and AUC 0-72 to the Labrasol solution.
  • the analytes, enzalutamide, MDPC0002, and MDPC0001 and internal standards (IS), N- 13 CD 3 -enzalutamide, MDPC0002- 13 CD 3 , and MDPC0001- 13 CD 3 were extracted from 0.050 ⁇ L of rat plasma by a liquid-liquid extraction procedure. Internal standard working solution (25.0 ⁇ L) was added to all wells except the matrix blank. A 25.0- ⁇ L volume of acetonitrile was added all matrix blank samples. After adding 200 ⁇ L of 5% sodium bicarbonate in water buffer solution, the plate was vortexed for approximately 10 seconds.
  • a Tomtec Quadra 96-well pipettor was used to add 1.050 mL of methyl tert-butyl ether (MTBE) to all wells, mixed, and approximately 1.00 mL of the organic layer was transferred to a clean 96-well plate.
  • the samples were evaporated under heated nitrogen and reconstituted with 250 ⁇ L of 0.1% formic acid in methanol/water (40:60, v/v). The plate was covered and gently vortexed for approximately 10 seconds.
  • the extracts were chromatographed under reverse phase conditions on an ACE 5 C18 HPLC 5 ⁇ m, 2.1 ⁇ 30 mm column.
  • the compounds were detected and quantified by tandem mass spectrometry in positive ion mode on an MDS Sciex API 3000 equipped with a Turbo IONSPRAY ® probe. Calibration curves were obtained by performing a linear regression (weighted 1/x 2 ) of the data from the calibration standards.
  • Plasma enzalutamide concentration vs. time curves were prepared, and values for the following parameters were determined.
  • C max is the highest enzalutamide concentration observed for each rat.
  • Tmax is the time that C max is first achieved.
  • AUC 0-72 is the area under the plasma enzalutamide concentration vs. time plot out to 72 hr post-dosing.
  • Pharmacokinetic data for the formulations studied are presented in Table 13.1.
  • Table 13.1. Mean AUC 0-inf and % Bioavailability in rats for enzalutamide formulations. Crystalline drug, amorphous drug, and HME dispersion formulations were dosed in suspension in a 0.5% methylcellulose vehicle.
  • Tablets containing enzalutamide/Polymer spray-dried dispersions Tablets containing enzalutamide/Polymer spray-dried dispersions.
  • Enzalutamide tablets were prepared by direct compression, from the formulation in Table 14.1. Table 14.1. Tablet composition.
  • Component Quantity mg/tablet
  • 60%A enzalutamide/HPMCAS-M SDD 266.7 Colloid silicon dioxide (Cab-O-Sil M5P)
  • Microcrystalline cellulose Avicel PH102
  • Lactose monohydrate spray-dried
  • Croscarmellose sodium Ac-Di-Sol
  • the solid amorphous dispersion was added to an appropriate container.
  • a portion of the solid amorphous dispersion (approximately 3 to 10 times the weight of colloidal silicon dioxide) was added to an LDPE bag containing the colloidal silicon dioxide.
  • the SDD was manually mixed with the silicon dioxide for approximately 2 minutes.
  • the mixture was passed through a No. 30 mesh screen, and added to the container.
  • the mixture was blended for 15 minutes at 12 rpm using a Turbula mixer.
  • Microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium were added to the container, and the mixture was blended for 15 minutes.
  • the mixture was subjected to high-shear mixing by passing it through a Comil 197 equipped with a 0.032-inch screen and 1601 impeller (impeller speed 1000 rpm). Since the Comil has a chamber diameter of 2.2 inches, the Froude Number for this high-shear mixing is about 125.
  • the milled material was added to a container. A portion (approximately 3 to 10 times the weight of magnesium stearate) was added to an LDPE bag containing the magnesium stearate. The material was manually mixed with the magnesium stearate for approximately 30 seconds to 2 minutes, passed through a No. 20 mesh screen, and added to the container. The mixture was blended for 5 minutes at 12 rpm using a Turbula mixer.
  • Tablets were compressed using a rotary single-layer press, with 13/32" standard round convex tooling. Tablets weighed 500 mg each, with a hardness of 12 to 16 kP.
  • Example 14 tablet blend was evaluated using the Carr's index calculated from bulk and tap density.
  • Bulk Density Weight of Sample g ⁇ Volume of Sample cc
  • Table A Carr's Index Formulation Carr's Index 60%enzalutamide:HPMCAS-M SDD 33.3%
  • Example 14 tablet blend made with colloidal silicon dioxide and high-shear mixing) 24.2%
  • the lower Carr's index of the formulation of Example 14 demonstrates improved flow properties of the dispersion, which enables tablet formation using a direct compression Process.
  • the reference formulation was a liquid-filled, soft gelatin capsule containing 40 mg enzalutamide dissolved in Labrasol; four such capsules are required to deliver a 160 mg dose.
  • the test formulation was a tablet containing 160 mg enzalutamide in the form of a 60%A:HPMCAS-M spray-dried dispersion.
  • the liquid-filled capsule formulation had previously been used in clinical studies in castration-resistant prostate cancer.
  • the four-capsule regimen is inconvenient because of the number of capsules that must be taken, particularly in the light of the fact that cancer patients have to take multiple drugs.
  • the objectives of the human pharmacokinetics study were as follows:
  • the fasted conditions involved an overnight fast from food (minimum 10 hours) prior to dosing, and the fed conditions involved a standard high-fat, high-calorie meal that was ingested within 30 minutes prior to dosing.
  • the high-fat, high-calorie meal was described in " US FDA Guidance for Industry: Food Effect Bioavailability and Fed Bioequivalence Studies (December 2002 )."
  • the clinical research personnel administered the study medication at approximately 0800 hours with ambient temperature water to a total volume of about 240 mL. Subjects were required to swallow the study medication whole and not chew the medication prior to swallowing. The subjects were required to refrain from drinking beverages other than water during the first 4 hours after dosing. Water was allowed except 1 hour pre and post dose. Lunch was served ⁇ 4 hours post dose, and dinner was served ⁇ 9 to 10 hours post dose.
  • Plasma isolated from the whole blood samples was analyzed for concentrations of enzalutamide and its metabolites MDPC0001 and MDPC0002 using a sensitive, specific, and validated assay based on liquid chromatography and tandem mass spectroscopy (LC/MS/MS).
  • the analytes, enzalutamide, MDPC0002, and MDPC0001 and internal standards (IS), N 13CD3 enzalutamide, MDPC0002 13CD3, and MDPC0001-13CD3 were extracted from 0.050 ⁇ L of plasma by a liquid extraction procedure. Internal standard working solution (25.0 ⁇ L) was added to all wells except the matrix blank. A 25.0- ⁇ L volume of acetonitrile was added all matrix blank samples.
  • the compounds were detected and quantified by tandem mass spectrometry in positive ion mode on an MDS Sciex API 3000 equipped with a Turbo IONSPRAY ® probe. Calibration curves were obtained by performing a linear regression (weighted 1/x2) of the data from the calibration standards.
  • Ratio of least squares means (Test/Reference) based on crossover-treatment bioequivalence statistical tests.
  • c Median (range).
  • Ratio of least squares means (Test/Reference) based on parallel-treatment bioequivalence statistical tests.
  • enzalutamide MDV3100
  • 3 parts by weight of hydroxypropylmethylcellulose acetate succinate HPMCAS-MG,Shin-Etsu Chemical Co.,Ltd.; the same was used hereafter
  • a spray dryer QSD-0.8-CC, GEA
  • the mixture was formed into granules using dry granulation machine (roller compactor, TF-MINI, FREUND). After the resulting granules were mixed with croscarmellose sodium and magnesium stearate, the mixture was formed into tablets using a rotary tableting machine to obtain a tablet containing the solid dispersion. After tableting, the tablet was filmcoated by using filmcoating machine(HCT-30 Hi coater 30, FREUND). The formulation is shown in Table 16.
  • Example 16 Example 17
  • Example 18 Example 21
  • Example 22 Example 23 enzalutamide 80.0 80.0 80.0 160 80.0 80.0 hydroxypropyl methylcellulose acetate succinate 240.0 240.0 160.0 106.7 400.0 80.0 hypromellose - - - - - 160.0 calcium hydrogen phosphate hydrate 160.6 160.6 240.6 - 54.0 256.0 colloidal silicon dioxide - - - 2.5 - - light anhydrous silicic acid - - - - - 16.0 microcrystalline cellulose - - - 94.8 - - lactose monohydrate - - - 94.7 - - crospovidone - - - - - 40.0 croscarmellose sodium 54.0 54.0 54.0 40.0 60.0 160.0 magnesium stearate 5.4 5.4 5.4 1.30 6.0 8.0 filmcoating agent - 16.2 - 17.5 18.0 24.0 total (mg) 540.0 556.2 540.0 517.5 618.0 824.0 tablet size 1
  • Example 16 After 1 part by weight of enzalutamide and 2 parts by weight of hydroxypropylmethylcellulose acetate succinate were dissolved in acetone, a spray dryer (QSD-0.8-CC, GEA) was used to obtain a solid dispersion. Further, a tablet was prepared as the same method as Example 16. The formulation is shown in Table 16.
  • a solid dispersion which comprises 1 part by weight of enzalutamide and 1.5 part by weight of hydroxypropylmethylcellulose acetate succinate, was prepared as the same method as Example 18.
  • a solid dispersion which comprises 1 part by weight of enzalutamide and 1 part by weight of hydroxypropylmethylcellulose acetate succinate, was prepared as the same method as Example 18.
  • a solid dispersion which comprises 1 part by weight of enzalutamide and 0.67 part by weight of hydroxypropylmethylcellulose acetate succinate, was prepared as the same method as Example 18.
  • the solid dispersion was mixed with colloidal silicon dioxide. Microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium are added to the mixture and blending is continued. The mixture is then milled. After magnesium stearate is mixed with the milled mixture, core tablets are compressed on a tablet press. The tablet was filmcoated by using filmcoating machine.
  • the mixture was formed into granules using dry granulation machine (roller compactor, TF-MINI, FREUND). After the resulting granules were mixed with croscarmellose sodium and magnesium stearate, the mixture was formed into tablets using a rotary tableting machine to obtain a tablet containing the solid dispersion. After tableting, the tablet was film-coated by using film-coating machine (HCT-30 Hi coater 30, FREUND). The formulation is shown in Table 16.
  • the mixture was formed into granules using a dry granulation machine (roller compactor, TF-MINI, FREUND). After the resulting granules were mixed with croscarmellose sodium , crospovidone and magnesium stearate , the mixture was formed into tablets using a rotary tableting machine to obtain a tablet containing the solid dispersion. After tableting, the tablet was film-coated by using film-coating machine (HCT-30 Hi coater 30, FREUND). The formulation is shown in Table 16.
  • Enzalutamide and the polymer were dissolved in 2mL of 50% acetone and 50% USP 6.8 buffer.
  • the polymer was used each of hydroxypropylmethylcellulose 2910 (TC-5E, Shin-Etsu Chemical Co., Ltd.), hydroxypropylmethylcellulose 2910 (TC-5R, Shin-Etsu Chemical Co., Ltd.), polyvinylpyrrolidone(Kollidon, BASF), copolyvidone (Kollidon VA-64, BASF), hydroxypropylmethylcellulose acetate succinate(HPMCAS-MG,Shin-Etsu Chemical Co.,Ltd ) and was dissolved in 500 mL of a second fluid for disintegrating test used in a dissolution test described in the Japanese Pharmacopoeia fifteenth edition. For comparison, 2 mL of 50% acetone and 50% USP 6.8 buffer dispersed enzalutamide without such polymers was prepared.
  • Table 17 polymer solubility ( ⁇ g/mL) hydroxypropylmethylcellulose 2910 (TC-5E) 42.7 hydroxypropylmethylcellulose 2910 (TC-5R) 39.2 polyvinylpyrrolidone 40.1 copolyvidone 47.4 hydroxypropylmethylcellulose acetate succinate 31.1 without polymer 29.0
  • a drug release property from each of the solid dispersion prepared in Examples 17 to 22 or each of the tablet prepared in Examples 16, 18 and 21 was evaluated by a liquid-replacement dissolution test, in which a paddle method (50rpm) was started using 300mL of 0.03N hydrochloric acid (pHl .2), and the liquid conditions for the dissolution test were changed to pH6.8 and 900mL 30 minutes after the beginning of the USP 34-NF 29. The drug release property was evaluated.
  • the dissolution profiles of the enzalutamide from the solid dispersion and the tablet are shown in Figure 3 , Figure 4 , respectively.
  • Example 17 The tablet obtained in Example 17 was subjected to a dissolution test to study their dissolution immediately after formulation (at the start of storage) and after storage at 40°C and 75% relative humidity for 1 month.
  • the dissolution test was accomplished by the paddle method described the United States Pharmacopoeia.
  • a liquid-replacement dissolution test in which a paddle method (50rpm) was started using 300mL of 0.03N hydrochloric acid (pH1.2), and the liquid conditions for the dissolution test were changed to pH6.8 and 900mL 30 minutes after the beginning of the USP 34-NF 29.
  • the drug release property was evaluated.
  • the dissolution profile is shown in Figure 5 .
  • the tablets prepared in Examples 16, 18, 21, 22 and 23 and a soft capsule for control were orally administered to dogs.
  • the formulation of the soft capsule is shown in Table 18. Percentage of blood exposure of enzalutamide compared to the soft capsule, %AUC and %C max , were evaluated.
  • test formulations were administered with 50 mL water to dogs had been fasted over night.
  • the test formulations were used one tablet in case of the tablet comprised 160mg enzalutamide (Example 21), two tablets in case of the tablet comprised 80mg enzalutamide (Example 16, 18, 22 and 23), or four capsules comprised 40mg enzalutamide for control.
  • test formulations After orally administered the test formulations, blood samples were collected with time. A drug concentration in the plasma (ng/mL) was measured and calculated maximum drug concentration(Cmax) and AUC for 168 hr (AUC 0-168h:ng ⁇ h/mL). The dogs adjusted acid condition in the stomach were used in this test on the assumption of healthy individuals.
  • Example 16 The solid dispersions prepared in Examples 16 ,18, , 22 and 23and crystalline enzalutamide were evaluated for crystallinity using X rays.
  • the solid dispersions prepared in Examples 16, 18, 22 and 23 were amorphous.
  • the tablet obtained by storing the solid dispersion prepared in Example 17 at 40°C and 75% relative humidity for 1 month in Example 17 was also amorphous.
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